Shape changing drug delivery devices and methods

ABSTRACT

Drug delivery using bio-affecting drugs, particularly with shape changing drug delivery devices. Embodiments are included for depots for delivery of a therapeutic agent that change from an elongated state ex vivo to a coil in vivo where the agent is released.

CROSS REFERENCE TO RELATED APPLICATIONS

This patent application claims priority to U.S. Provisional ApplicationNo. 62/260,068 filed Nov. 25, 2015 and U.S. Provisional Application No.62/319,033 filed Apr. 6, 2016, which are hereby incorporated byreference herein.

TECHNICAL FIELD

The technical field is related to drug delivery using bio-affectingdrugs.

BACKGROUND

Drug delivery is the art of making and using formulations, technologies,and systems for transporting a therapeutic agent in the body as neededto safely achieve its desired therapeutic effect. Drug delivery is anactive field involving many scientists and scientific disciplines. Thereis an ongoing need to find new and better ways to deliver therapeuticagents.

SUMMARY OF THE INVENTION

Placement and successful use of a drug delivery device in an eye ischallenging because the interior of the eye is very sensitive to foreignbodies, has a limited volume, and tissue trauma from surgicalimplantation procedures can have important sequellae. Depots that have aslim profile to facilitate placement and a different, compactspace-saving shape after placement are described herein for delivery ofTKIs or other therapeutic agents, e.g., proteins, antibodies, orantibody fragments. An embodiment of the vehicle component of drugdepots is a highly biocompatible material shaped as a thin rod ex vivobut transforms into a curved, coiled, or even helical, hydrogel in vivo.The hydrogel matrix and the TKI or other agent can be chosen to provideconditions suitable for controlled drug delivery, even over a timeperiod of many months. Materials and methods of drug delivery are setforth herein that are useful in the eye and are generally useful in thebody. Hydrogels that curl into complex shapes are described herein thathave various advantages as vehicles for delivery of agents.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a perspective view of a human eye;

FIG. 2 is a partial cut-away perspective view of a human eye, depictinga hypodermic needle penetrating into the intraocular space for placementof a drug delivery device;

FIG. 3 is a cross-sectional view of a human eye;

FIG. 4 is an illustration of a rod-shaped depot with a plurality ofscores or weakened areas that facilitate a change of the rod's shape inaqueous solution to a curved shaped depot

FIG. 5 is an illustration of a rod-shaped depot made of two layers ofdifferent vehicle materials, with the vehicle materials having differentcoefficients of swelling or elongation, so that the depot changes shapeafter exposure to aqueous solution;

FIG. 6 is an illustration of a rod-shaped depot made with one materialmaking a layer around another material, with the materials havingdifferent coefficients of swelling or elongation, so that the depotchanges shape after exposure to aqueous solution;

FIGS. 7A-7B set forth processes of making the vehicles of FIG. 5 or 6;

FIG. 8 illustrates a process of making a vehicle as in FIG. 6;

FIG. 9 is a photomicrograph of a dried vehicle comprising a secondmaterial disposed as a layer over a first material, prepared as setforth in Example 1; 30× magnification, with diameter dimensionmeasurements;

FIGS. 10A-10C depicts three successive images that show the change ofthe vehicle of FIG. 9 from an initial rod shape to a helical shape inaqueous physiological buffered saline solution;

FIGS. 11A-11C depict three successive images that show the change of thevehicle of FIG. 9 from an initial rod shape to a helical shape in aviscous, aqueous physiological buffered saline solution that compriseshyaluronic acid;

FIGS. 12A-12D depict four successive images that show the change of theshape of a vehicle prepared as described in Example 1 from an initialrod shape to a helical shape in a rabbit eye;

FIG. 13A is a photograph of a vehicle made according to Example 3A;

FIG. 13B is a photograph of a vehicle made according to Example 3B;

FIGS. 13C-13D are two images of a single coiled fiber made according toExample 3B;

FIGS. 14A-14B are illustrations of the dimensions of a hydrated, coiledfiber made according to Example 6, at t=30 minutes;

FIGS. 15A-15F are photographs of a process of making a fiber depot asset forth in Example 10;

FIGS. 16A-16C are images of a dry fiber depot and a hydrated, coiledfiber depot made by the process of Example 11; before (16A) or after(16B, 16C) hydration;

FIGS. 17A-17B are images of a hydrogel depot with a drug-loaded coatingin a crescent shape with fast-degrading necked fiber already degraded,leaving an empty column along the length of the fiber, in side view(17A) and end view (17B);

FIG. 18A is an image of a dry fiber depot (coating and necked fibersystem) loaded into a 27 gauge TW needle;

FIG. 18B is an image of a hydrated and coiled fiber depot on a fingertip(agent: axitinib);

FIGS. 18C-18D are photomicrograph images of hydrated coiled fiber depots(drug: axitinib).

FIG. 19 provides results of an experiment set forth in Example 13, withmultiple fibers coated by an outer hydrogel containing bovine IgG spraydried particles, showing a time required to form the coil shape;

FIG. 20 provides results of an experiment set forth in Example 14, withvehicles of various diameters correlated to a time required to form thecoil shape depot containing bovine IgG;

FIG. 21 provides results of a first series of experiment set forth inExample 15 for multiple fibers being introduced serially in the depot,in consideration of the volume and working area of an eye;

FIG. 22 provides results of a second series of experiments set forth inExample 16 for multiple fibers being introduced serially into the depot,in consideration of the volume and working area of an eye;

FIG. 23 is an illustration of a necking mechanism for a dry fiber;

FIG. 24 is an illustration of the role of crystallinity in a neckingprocess. The crystalline regions providing dimensional stability to thedepot, until the depot is placed in solvent (e.g. water or body fluid)or heated above the melting point;

FIGS. 25A-25C are photomicrographs of an in vivo drug delivery test ofnecked vehicles as set forth in Example 17; and

FIGS. 26A-26C are photomicrographs of an in vivo drug delivery test ofcoiled bipolymer as set forth in Example 17.

DETAILED DESCRIPTION

Drug delivery to the eye is an active field. Improvements in drugs fortreatment of eye diseases have created new options for patients,including controlled release devices. Some ocular drug delivery deviceswere like traditional drug delivery devices, for instance, a drug wasreleased from a chamber through a membrane or by osmotic pumping. Thesehave certain limitations, however, including a limited volume that canbe tolerated by the eye. Another approach to ocular extended release wasto put drugs into degradable particles that were injected into the eye.There were sometimes problems, however, with the particles settling ontothe retina and causing contact toxicity. Innovators in this field thencreated small drug delivery devices that are biodegradable rods ofpoly(lactic-co-glycolic acid) copolymers (PLA/PGA) that are impregnatedwith drugs and inserted into the eye. As they erode, the drug is able tomove out of the PLA/PGA matrix, so that the degradation controls therate of release. These devices are effective to provide extended releaseas they are eroded by the aqueous solution in the eye. Another approachhas involved the use of certain hydrogels that are formed in situ orthat use various controlled release techniques, as in US 2009/0252781,US 2013/0071462, U.S. Pat. No. 8,961,501, or US 2013/0156725. However,there are further techniques that can be used to increase the range ofclinical treatments that can be made with controlled release devices forthe eye. FIGS. 1-3, discussed below, show the eye's anatomy. These sametechniques can be extended to other tissues.

FIG. 4 depicts one technique to make a hydrogel with a precise curve. Aswellable hydrogel or a xerogel 100 that forms a hydrogel in aqueoussolution is prepared with a plurality of weakened areas 102. The termxerogel, as used herein, refers to a material that forms a hydrogel inaqueous solution, regardless of whether it was created as an organogelor hydrogel. When swellable vehicle 100 swells in aqueous solution, itadopts a curved shape 104. The weakened area may be, e.g., a tear,crack, or void, (collectively referred to as notches). The notch can beperformed with a tool applied directly to a site of the intended notchor other weakened area or indirectly by stretching the fiber to formnecks and/or notches. FIG. 5 depicts another technique wherein twohydrogels 110, 112 are joined together to form a biopolymer hydrogel orxerogel 114. In aqueous solution, hydrogel 110 elongates more thanhydrogel 112 and the material 114 forms a more complex shape, e.g., aring 114′ or a coiled 114″ shape. This bipolymer technique may becombined with notching or weakening. A pairing of two hydrogels hereinis referred to as bipolymeric although they may be formed from the sameor from different precursors; the processing conditions and details ofstructure of the hydrogels can be manipulated to give them differentproperties. Moreover, besides using two hydrogels, a plurality ofhydrogels may be used to make a multipolymeric material and the termbipolymer is not limited to two hydrogels.

FIG. 6 depicts an embedded biopolymer technique, wherein a firsthydrogel 122 is encapsulated with another hydrogel 124 to make vehicle126. In this context, encapsulated means that one of the hydrogels isinside the other, although there may be some portions that are thinlycovered or not at all covered by the encapsulating polymer: theencapsulation does not have to be complete. The term substantiallycompletely encapsulated means at least about 90% of a surface area of ahydrogel is covered-up by the encapsulating material. Encapsulation canprovide improved unity between the two hydrogels, with the encapsulatedhydrogel being unable to be released if there is low adherence orslipping at the interface with the other hydrogel. One or more hydrogelscan be encapsulated by an encapsulating hydrogel, with a plurality ofthe encapsulated hydrogels providing greater mechanical unity and/orincreased curvatures or a faster rate of curling when placed intosolution. In this instance, hydrogel 122 has a lesser coefficient ofelongation relative to hydrogel 124. Hydrogel 124 is prepared to be axerogel, or as a hydrogel that is less than fully hydrated relative toits equilibrium hydration in a physiological solution, and is placedinto a tissue where it imbibes a physiological solution, which isassumed to be aqueous. The inside hydrogel 122 does not elongate as muchas outer hydrogel 124; consequently the swollen bipolymer hydrogel 126adopts a curved shape, e.g., coil 126; or ring shape 126″. The term ringis broad and includes portions of a circle, e.g., C-ring, half-ring, ora complete ring.

FIG. 7A is a flowchart exemplifying how to make a shape-changinghydrogel material. A precursor (meaning one or more precursors, as maybe needed to make a crosslinked matrix) is prepared in a solution(aqueous or organic) and reacted in a mold. The mold may be a tube orother shape. The matrix is dried, with lyophilization being a usefultechnique. Zones of weakness are directly or indirectly created. Whenhydrated, the weakness provides for irregular shapes to be formed, orpredetermined shapes for zones created with a particular shape as an endgoal. In contrast, a hydrogel made without a weak area will tend tochange shape uniformly, usually by swelling in all directions unlesssteps have been taken to make it preferentially swell in certaindimensions, or even to shrink in some dimensions while swelling in otherdirections. Fibers that have been stretched to a necking point willexhibit shrinkage in length when exposed to aqueous solution or solventsthat wet the matrix; necking is discussed in detail below.

FIG. 7B is a flowchart for a process of making a bipolymer material.Precursors are crosslinked to form a hydrogel or organogel matrix. Theresultant matrix is dried. Optionally, it may be treated to createweakened areas. In this embodiment, the matrix (typically a rod orstrand) is secured on its ends to prevent its length from decreasing,particularly if it has been stretched, as in this embodiment. A secondprecursor is introduced into the mold and is crosslinked around thefirst matrix. The solvent for the second precursor will generally be onethat wets the matrix of the first matrix, which will exhibit a tendencyto shrink but cannot do so because it is secured at its ends. Theinterior hydrogel may be in the center of the mold or in contact with aside of the mold. The outer matrix and the inner matrix are chosen tohave different swelling and/or shrinking properties. When these aresufficiently different, the resultant bipolymer material will exhibit acomplex or precisely engineered shape upon hydration. An example of acomplex shape is a shape that, due to an increased effectivecross-section, has an increased resistance to movement through fluid,especially viscous fluid such as found in a vitreous humor. Accordingly,a complex shape includes shapes that, relative to a sphere or a rod,have a drag coefficient that is increased by a factor of 1.5 to 100;Artisans will immediately appreciate that all ranges and values betweenthe explicitly stated bounds are contemplated, with, e.g., any of thefollowing being available as an upper or lower limit: 1.5, 2, 3, 5, 10,20, 25, 50, 75, 90, 100. Artisans will appreciate how to makemultipolymer materials, e.g., by making a plurality of rods or strandsand encapsulating them in an encapsulating matrix.

FIG. 8 is an illustration of various embodiments for making a bi- ormultipolymer. A precursor may be crosslinked to form matrix 150 that isstretched 150′ while it is still wet. This matrix 150′ can then coatedwith another precursor that forms second matrix 160 to make bipolymervehicle 162 by coating it (a broad term including encapsulation).Alternatively, stretched matrix 150′ can be dried and held at a constantlength, or otherwise limited during drying to shrinking less than itwould otherwise do so, to form dried stretched matrix 150″. Matrix 150″can, in turn, be used to make bipolymer vehicle 162. Alternatively,matrix 150″ can be rehydrated and allowed to shrink to form hydratedmatrix 154, which can be used in a biopolymer or other purposes (notshown). The agent can be in the inner and/or outer hydrogel, eitherdirectly in the matrix or in an encapsulated form.

Example 1 describes the making of a bipolymer fiber that adopts a coiledshape upon hydration. A first solution was made from an electrophilicprecursor (a multiarmed polyethylene glycol terminated with succinimidylglutarate) and second solution was made with an electrophilic precursor(a multiarmed polyethylene glycol terminated with amines). The solutionswere mixed and introduced into a tubular mold. The precursorscrosslinked to form a matrix that was dried into a fiber shape. Thefiber was stretched to about four times its original length and wasobserved to undergo necking, which is discussed elsewhere herein. Thefiber was placed into a long tubular mold with its ends exposed, pulledtaut, and the ends were secured. The tubular mold was bent around acurved surface so that the fiber was held to one of the sides of themold. A mixture of electrophilic and nucleophilic precursors wasinjected into the mold and allowed to crosslink in contact with thedried fiber. The resultant material was dried and cut into 1 cm lengths,and had a diameter of 0.12-0.15 mm (FIG. 9). The bipolymer vehiclecoiled into a helical shape within 10 seconds of exposure to aphysiological buffer solution (FIGS. 10A-10C), even in a highly viscoussolution (FIGS. 11A-11C). When injected into a rabbit eye, FIGS.12A-12D, the bipolymer vehicle rapidly coiled as it was ejected from theneedle, within about 15 seconds. Examples 3A (FIG. 13A) and 3B (FIGS.13B-13D) demonstrate further embodiments of the making of a bipolymervehicle.

Examples 4-6 were biopolymers made with axitinib or IgG as model agents;the agents were loaded at effective concentrations without comprisingthe shape-changing properties of the biopolymers. The bipolymer vehicleof Example 6 (FIGS. 13B-13D) comprised fluorescein and its dimensionswere measured in detail (FIGS. 14A-14B).

Example 7 described the making of a bipolymer vehicle with a rapidlydegrading necked interior hydrogel. The exterior hydrogel comprises theagent to be delivered. The interior hydrogel degrades, resulting inincreased exposed surface area once the necked portion has dissolved.Changing the geometry of the necked portion, particularly the diameter,changes the available drug delivery surface area. Example 8 presents afurther embodiment, and Example 9 has details for a process ofmicronizing a therapeutic agent by precipitation. Examples 10 (FIGS.15A-15F) and 11 detail various methods of making bipolymer vehicles.FIGS. 16A-16B, 17A-17B, and 18A-18D are further images of bipolymervehicles made by these various processes.

Example 12 reports the results of tests on biopolymers made according toExamples 3A and 3B. It was observed that a hydrogel that was derivedfrom an organogel had a longer persistence in vivo as compared to ahydrogel that was derived from a hydrogel. This result showed that it ispossible to use the same precursors in both an interior hydrogel and inan exterior hydrogel of a bipolymer vehicle. The organogel derivedhydrogel is believed to last longer due to a higher degree ofcrosslinking achieved in the organic solvent, which was anhydrous. Abipolymer vehicle can therefore maintain a coiled form until the outerhydrogel is fully degraded. This feature is useful because earlydegradation of the interior hydrogel allows the outer hydrogel to changeinto a less compact shape, e.g., uncoil, which is not desirable in aconfined space such as a vitreous humor.

Example 13 (FIG. 19) describes a series of bipolymer vehicles made witha varying number of encapsulated hydrogels. It was observed thatincreasing a number of the interior hydrogels accelerated the rate ofcoiling. Fast coiling is advantageous for introduction into a sensitivearea such as an eye because the coiling will take place quickly andminimize potential harm to the tissue that could be caused by a rapidintroduction of slower coiling depots. Example 14 (FIG. 20) describes aseries of bipolymer vehicles made with varying diameters of encapsulatedhydrogels while an outer dimension of the vehicle was held constant.Larger inner hydrogels provided faster coiling. Coil times were lessthan 30 seconds; Artisans will immediately appreciate that all rangesand values between the explicitly stated bounds are contemplated, with,e.g., any of the following being available as an upper or lower limit:30, 25, 20, 15, 10, 5, 4, 3, 2, 1 seconds.

Examples 15 and 16 (FIGS. 21-22) describe use of a plurality ofbipolymers to provide a vehicle. Instead of placing a monolithic (onlyone in number) bipolymer vehicle, a plurality of bipolymer segments areprovided. A rod or a long fiber can be cut into multiple segments toenable injection into cavities or spaces that are limited in size. Forexample, the eye has about a 24 mm inside diameter. Injecting a 60 mmfiber would potentially impinge on the distal retina if it did not coilquickly enough, causing damage to the delicate tissue. The segments canbe cut to less than 24 mm and placed end to end in an applicator lumen(e.g. a hypodermic needle). The segments may be designed to slideparallel to each other as they exit the applicator so that they coilinto a single mass, due to entanglement. The fiber may be cut on anangle to facilitate a sideways movement relative to the precedingsegment as they exit the lumen of the applicator into the eye, so thefollowing segment stops pushing the preceding segment and slidesalongside it. Thus, an equal mass of depot can be safely administered.It was observed that the rate of fiber entanglement post injection andalso the fiber injection distance decreased as fiber segment lengthdecreased. A decreased fiber injection distance creates a saferinjection with lower risks of fiber segments pushing each other (termedfiber training) and contacting the interior walls of the eye. It wasfurther observed that cutting the ends of the fiber at an angle could beused to reduce fiber training, with an angle ranging from more than 30to less than 60 being useful (perpendicular cut is 0 degrees); Artisanswill immediately appreciate that all ranges and values between theexplicitly stated bounds are contemplated, with, e.g., any of thefollowing being available as an upper or lower limit: 30, 31, 35, 40,45, 50, 52.5, 55, 59, 60 degrees. Embodiments include a plurality ofvehicles that collectively are administered to a tissue, with thevehicles comprising such an angle and being delivered together in asingle injection or other single administration.

FIG. 23 illustrates necking, which is a term that describes plasticdeformation of the hydrogel/xerogel/organogel as it is stretched. As thefiber is stretched, it will begin to elongate and become thinner. Thematrix is crosslinked, so pulling it longitudinally causes a collapse ofthe diameter (or other width for a non-circular object). The thinnedportion experiences orientation of the matrix. Embodiments include acrosslinked hydrogel/xerogel/organogel matrix of a semicrystallinematerial that has been pulled in the axial direction to cause necking tooccur. The term semicrystalline is known in the polymer arts. FIG. 24depicts orientation of a semicrystalline matrix. As formed, the matrixis a crosslink of polymers in a random coil configuration. Whenstretched, the matrix orients along the axis of stretching. If dried,the matrix keeps this shape because of the association of microdomainsin the matrix, particularly crystals that form between polymers. Forexample, a polymeric material that crystallizes or has increasedcrystallization when stretched will decrease in length when theconditions are changed to allow the crystallinity to decrease. Vehicles(hydrogels or organogels) can be stretched and dried and allowed tocrystallize to a semicrystalline, dimensionally stable configuration sothat, upon hydration, the vehicles will contract as the crystallizeddomains decrease. Alternatively, vehicles comprising hydrogels ororganogels can be dried to xerogels and allowed to crystallize and thenstretched (optionally with heating) to a semicrystalline, dimensionallystable rod, upon hydration, the vehicles will contract as thecrystallized domains decrease. Or a crosslinked hydrogel or organogelcan be stretched while wet to a specific length and held at that lengthuntil the solvent has evaporated leaving the semicrystalline, orientedfiber. Alternatively, the crosslinked hydrogel or organogel can beallowed to dry to an unoriented fiber or rod that is semicrystalline.Upon drawing, the fiber will neck to a characteristic draw ratio that isdependent on the molecular weight between crosslinks. The addition of atherapeutic agent or other material also influences the characteristicnecking draw ratio, with experiments showing that effective amounts ofthe agents can be accommodated without undue disruption of neckingstructure.

Example 17 describes an in vivo test for delivery of a therapeutic agentfrom a necked rod (FIGS. 25A-25C) or a coiling bipolymer (FIGS.26A-26C). The vehicles rapidly hydrated upon placement in the vitreousand delivered more than 4000× an effective amount for six months. Thedelivery time could readily be adjusted for longer times of delivery ofan effective concentration of the agent by increasing persistence of thematrices. Axitinib was chosen as a clinically relevant model for thesetests. The delivered amounts are not toxic.

Shape Changing Devices

Drug delivery depots may be created that have a first shape ex vivo andchange to a second shape in vivo. An initial thin and elongated shape isuseful for placement because it minimizes trauma of placement into thetarget tissue. The second shape provides advantages such as a morecompact shape or a shape with advantages for the targeted space. Forinstance a change in shape after placement in an ear cavity can aid inretention, or a change of shape after placement in a sinus cavity canaid retention and delivery of drugs. In the context of an eye, a compactshape allows for the device to be out of visual pathway and to resistmigration over time. Embodiments include providing a shape and/or avolume change of the vehicle that reduces a tendency of the vehicle tomigrate from the site where it is initially placed in a tissue or tissuefluid compared to an object of the shape and dimensions of the vehiclebefore the shape change. Accordingly, an object that is not straight, isnot round, is arbitrarily non-linearly folded, or is coiled can morereadily resist migration due to an increased effective cross-section,making it more resistant to movement through fluid, especially viscousfluid such as vitreous humor. Further, using a shape changing vehicleprovides for passing the vehicle through an opening and placement at atissue, with the change in shape and a volume change of the vehiclepreventing expulsion of the vehicle through the opening. The opening,for instance, may be a puncture, a puncture made with a needle, an entrywound, or a pre-existing passage. The term passage is a broad term thatincludes natural pores, passages created by trauma or disease, naturalor artificial lumens or voids.

An embodiment of the invention is a vehicle or prosthesis with aninitial aspect ratio that changes to a different aspect ratio(as-deployed or as-placed) after deployment. The aspect ratio of avehicle describes the proportional relationship between its shortestside and its longest side (maximum length). It is commonly expressed astwo numbers separated by a colon, as in 1:25. Embodiments include havingan aspect ratio before and after placement that is independentlyselected from 1:1 to 1:100,000; Artisans will immediately appreciatethat all ranges and values between the explicitly stated bounds arecontemplated, with, e.g., any of the following being available as anupper or lower limit: 1:2, 1:4, 1:10, 1:25, 1:50, 1:100, 1:200, 1:500,1:1000, 1:2000, 1:3000, 1:5000, 1:10000, 1:50000, 1:80000, 1:90000.Accordingly, embodiments include, for example, an initial aspect ratioof 1:100 and an aspect ratio after placement of 1:50.

The terms vehicle, depot, and prosthesis are used interchangeablyherein. A vehicle refers to a substance, usually without therapeuticaction, used as a medium to give bulk for the administration ofmedicines. A hydrogel that contains a drug for release is a vehicle. Theterm prosthesis similarly refers to a device that is used as a medicalaid. The term depot is a drug delivery construct comprising a vehicle orprosthesis and an active pharmaceutical agent.

An embodiment of the invention is a depot or prosthesis comprising avehicle shaped as a thin rod that curls to a curved shape afterplacement. The term curled is a broad term that refers to a curvedshape, which is a broad term that also includes more specific shapese.g., a coil, a spiral, a helix, a rolled sheet, a cylinder, or atwisted sheet as well as irregularly curved shapes such as straight rodchanged into a randomly curving structure. Embodiments include a vehiclewith an initial shape, before placement or after placement or acombination thereof of: a rod, sheet, curled sheet, rolled sheet,cylinder, prism (rectangular, cube, triangular, octagonal, etc.), sphere(perfect, ellipsoidal etc.), cone, curled, coil, curved, etc. The termrod is broad and refers to an object that is longer than it is wide,such as fibers or ribbons; the term is not limited to cylinders, so thecross-sectional shape can be varied. The term coiled, in the context ofa coiled vehicle, refers to a series of loops, including loops thatchange direction. For example, a coiled telephone cord has a series ofloops and can sometimes form loops that reverse direction, as in from aleft-handed to a right handed helix.

An embodiment of the invention is a depot or prosthesis comprising avehicle that has a first effective gauge that changes to a largereffective gauge after changing shape in response to the physiologicalfluid. The effective gauge of a depot or prosthesis is a term thatrefers to the smallest diameter passage of at least 5 mm in length thatthe depot or prosthesis can pass through without being deformed. Needlesare commonly rated according to a gauge, which is a measure of thelargest dimension of an object that could be passed through the needle.The nominal needle gauge rating is not necessarily the true effectivegauge of a needle because the needle has a nominal inner diameter and atolerance. Needle gauges are numerical values that increase as the outerdiameter of the needle decreases. The inner diameter of the needledepends on the needle gauge and the wall thickness, often referred to asregular wall, thin wall, extra-thin wall and ultra-thin wall by variousmanufacturers. In addition, the wall thickness is typically controlledto a tolerance, such that the depot or prosthesis diameter should be nogreater than the minimum diameter of the tolerance range of the needleinside diameter. Embodiments include a depot or prosthesis that has afirst effective gauge before deployment and a second effective gaugeafter deployment (after exposure to aqueous solution) independentlyselected from 0.001 mm to 10 mm; Artisans will immediately appreciatethat all ranges and values between the explicitly stated bounds arecontemplated, with, e.g., any of the following being available as anupper or lower limit: 0.005, 0.002, 0.003, 0.005, 0.01, 0.02, 0.03,0.04, 0.05, 0.07, 0.1, 0.15, 0.2, 0.25, 0.3, 0.5, 0.6, 0.8. 1, 1.5, 2,2.5, 3, 3.5, 4, 4.5 mm. In general the first effective gauge is smallerthan the effective gauge after deployment, although a vehicle thatchanges in the opposite direction may also be made and used. Embodimentsalso include a depot or prosthesis that can be introduced through aneedle having a gauge (referring to customary needle sizing) of 24, 25,26, 26 s, 27, 28, 29, 30, 31, 32, 33, or 34. As is evident, the vehiclesmay be chosen to have any combination of shape, aspect ratio, effectivegauge, or sizing before or after placement and such combinations may befreely mixed and matches as guided by the need to make an operableembodiment. Long rod shapes that shrink in length and increase in widthafter exposure to aqueous solution are useful in many situations.

An embodiment of the invention is a vehicle that comprises a firstmaterial with a first coefficient of elongation in physiologicalsolution and a second material that has a second coefficient ofelongation in physiological solution, with first and second coefficientsof elongation being different. The terms first material and secondmaterial are arbitrary to signify materials that are different incomposition and/or properties. The term coefficient of elongation of amaterial refers to change of length of the material in a dry state thatis placed into aqueous solution. The length refers to the most extendeddimension of an object. A coefficient of less than 1 means that thematerial becomes shorter when exposed to water; a coefficient of morethan 1 means that the material becomes longer. An embodiment of theinvention is a vehicle that comprises a first material that has a firstcoefficient of swelling in physiological solution and the secondmaterial has a second coefficient of swelling in physiological solution,with first and second coefficients of swelling being different. The termcoefficient of swelling of a material refers to a change of volume ofthe material in a dry state that is placed into aqueous solution. Acoefficient of less than 1 means that the material becomes smaller involume when exposed to water; a coefficient of more than 1 means thatthe material becomes larger in volume. A cross-linked semicrystallinematerial that has been stretched may have a coefficient of elongationless than 1, but a coefficient of swelling greater than 1. Thecoefficients are evaluated at physiological temperature.

The Examples provided herein provide multiple working embodiments. Anembodiment of making a shape-changing vehicle is to form a layer of asecond material around a first, stretched, material. The first materialis chosen and stretched so that it becomes shorter when exposed to aphysiological solution. The term layer is broad and refers to a completeencapsulation of one material by another, a partial overlay ofmaterials, a continuous contact area between materials, or a joining ofmaterials that contact with each other with or without overlap at allareas or having some zones of discontinuity in an otherwisecontacting-relationship.

The first material and the second material may be independently chosenfrom, for example: a hydrogel, an organogel, a xerogel, polylactic acid(PLA), polyglycolic acid (PGA), a copolymer of PLA and PGA (PLGA), aprecursor material as set forth herein, natural, synthetic, orbiosynthetic polymers. Natural polymers may include glycosminoglycans,polysaccharides, and proteins. Some examples of glycosaminoglycansinclude dermatan sulfate, hyaluronic acid, the chondroitin sulfates,chitin, heparin, keratan sulfate, keratosulfate, and derivativesthereof, other natural polysaccharides, such as carboxymethyl celluloseor oxidized regenerated cellulose, natural gum, agar, agrose, sodiumalginate, carrageenan, fucoidan, furcellaran, laminaran, hypnea,eucheuma, gum arabic, gum ghatti, gum karaya, gum tragacanth, locustbeam gum, arbinoglactan, pectin, amylopectin, gelatin, hydrophiliccolloids such as carboxymethyl cellulose gum or alginate gum crosslinkedwith a polyol such as propylene glycol, poly(hydroxyalkyl methacrylate),poly(electrolyte complexes), poly(vinylacetate) cross-linked withhydrolysable or otherwise degradable bonds, and water-swellable N-vinyllactams. Other hydrogels include hydrophilic hydrogels known asCARBOPOL®, an acidic carboxy polymer (Carbomer resins are high molecularweight, allylpentaerythritol-crosslinked, acrylic acid-based polymers,modified with C10-C30 alkyl acrylates), polyacrylamides, polyacrylicacid, starch graft copolymers, acrylate polymer, ester cross-linkedpolyglucan, a polyether, for example, polyalkylene oxides such aspolyethylene glycol (PEG), polyethylene oxide (PEO), polyethyleneoxide-co-polypropylene oxide (PPO), co-polyethylene oxide block orrandom copolymers, and polyvinyl alcohol (PVA), poly (vinylpyrrolidinone) (PVP), poly(amino acids) dextran, or a protein. amacromolecule, a crosslinkable, biodegradable, water-soluble macromer,natural proteins or polysaccharides may be adapted for use with thesemethods, e.g., collagens, fibrin(ogen)s, albumins, alginates, hyaluronicacid, and heparins a polyethylene glycol-containing precursor. Thehydrogels, organogels, and xerogels may comprise one more precursors asset forth below. An embodiment is a PLA fiber, PGA fiber, or a PLGAfiber coated with a hydrogel.

Embodiments include stretching polymeric materials until their structureis characterized by many small defects, such as tears, cracks, voids, orother weakened areas are set forth herein. The term necking, asdescribed herein, refers to such a stretching process. In general, ithas been found that it is useful to choose materials for stretching by alarge factor, e.g., by a factor of at least two, or 2-10: Artisans willimmediately appreciate that all ranges and values between the explicitlystated bounds are contemplated, with, e.g., any of the following beingavailable as an upper or lower limit: 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7,8, 9, 10. An alternative to a necking process is to mechanically orotherwise introduce weakened areas into a material, particularly a rod,without necessarily stretching the material. The material is chosenand/or processed so that, upon exposure to aqueous solution, it swells,contracts, or otherwise changes shape. The weakened areas direct theresultant forces to make a desired shape, e.g., curved, coiled, or asotherwise detailed herein.

An embodiment of a process to make a shape changing material is tostretch a first polymeric material and, while the material is maintainedunder tension or otherwise in the stretched configuration, make a layerof a second material that contacts the stretched material. The combinedbipolymeric material can be dried. The first material and the secondmaterial may be independently chosen to be, for example, a hydrogel oran organogel, in which case the dried product may comprise a xerogel.The first polymeric material may be stretched during its formation orafter it is formed, e.g., formed by casting, crosslinking, covalentcrosslinking, initiation of polymerization, or mixing precursors. Thestretching may take place while the material is wet or dry. One or moredrying steps may be performed, e.g., after making the first material(Material 1), after stretching Material 1, after forming the secondmaterial (Material 2), or after forming the combination bi-material. Theprocess may be adapted to comprise a plurality of polymers, meaning twoor more, e.g., 2, 3, 4, 5, etc. Formation, cross-linking, stretching,drying, and so forth may be performed in any order according to theprinciples outlined herein. The term bipolymeric means at least twopolymeric materials unless otherwise specified as being limited to 2materials.

The Material 2 layer may be on-center (concentric) or off-center(eccentric) on Material 1 (also referred to as a fiber in the case of arod shape), which will influence the final shape in vivo. For instance,the fiber (Material 1) may be concentric in a surrounding layer(Material 2), may be eccentric, or may have portions not contactingMaterial 2. The term layer is broad and includes continuous or partialcoatings.

Another embodiment of a shape-changing vehicle is a drug delivery depotcomprising a plurality of materials joined together that have differentcoefficients of swelling and/or coefficients of elongation. Forinstance, a plurality of hydrogel layers (organogel/hydrogel/xerogel)layers may be in contact with each other, made with differentswellability and/or stretched to different degrees by a necking or otherprocess to produce different coefficients of change (elongation orswelling). In use, the vehicle is placed at the intended site where itimbibes physiological solution and the mismatch of the joined materialselongation or swelling coefficients creates a curved and/or other shapechange. In addition, PLGA fibers, fibers with weakened areas or fibersegments may be used as low elongation elements with a higher or lowerelongation coefficient material bonded thereto, with the resultantcomposite material changing shape in response to a fluid.

A device may comprise two materials joined together that swelldifferently on exposure to aqueous solution. On exposure to water, thedifferential in swelling causes them to bend or otherwise change shape,e.g., curving or coiling. For example, a swellable hydrogel comprisinghydrophilic materials may be joined with a hydrogel or other materialthat swells to a lesser extent because it comprises hydrophobicmaterials, or comprises a lesser proportion of hydrophilic materials.More specifically, these could be, e.g., a first matrix of hydrophilicpolymers (polyethylene glycols or other hydrophilic materials set forthherein) joined to a second matrix that comprises hydrophobic polymers(PLURONICs or other hydrophobic materials set forth herein). If otherfactors are comparable, such as the degree of crosslinking and matrixorientiation, then the relatively more hydrophilic material will swellto a greater extent and the device will bend due to forces generated atthe interface between the materials.

A vehicle that comprises a first and a second material that are joinedtogether may be made with materials that degrade in vivo at differentrates. Embodiments comprising an inner material, e.g., a rod, and alayer in contact with the inner material may be chosen so that onedegrades before the other. The remaining material has an increasedsurface area in vivo, which affects a rate of drug delivery. Forinstance, embodiments with an inner material that shrinks in water tomake the vehicle assume a helical or more compact or alternative shapecan employ a rapidly degrading material for the inner material. Thus theremaining material, which may be the material with the drug or otheragent to be delivered, may have a surface area that increases by, e.g.,a factor from 1.5 to 3. Examples of relative rates of degradation are:from 1 to 10, e.g., a material that degrades 2× or 5× the rate of theother material.

The vehicles are useful as solids. The term solid means firm and stablein shape; not liquid or fluid; supports its own weight on a flat surfacewithout deformation although it may be elastically deformable, meaningthat it returns to its original shape after the deforming stress isremoved.

Vehicles that change shape can serve as depots for therapeutic agentsfor ocular drug delivery, drug delivery at a tissue or organ, or todeliver agents at other sites. Therapeutic agents (a term includingdrugs and also including active pharmaceutical agents (APIs) may beadded to the materials before, during, or after formation of thematerials. The agents may be added directly, as solids or suspensions orsolutes or colloids etc., or as embedded in drug vehicles, e.g.,degradable particles. Agents that are micronized, as per examples withaxitinib herein, are useful in many situations. Embodiments includeagents that are particles, or are in particles, that have a maximumdimension of 0.01 to 100 microns; Artisans will immediately appreciatethat all ranges and values between the explicitly stated bounds arecontemplated, with, e.g., any of the following being available as anupper or lower limit: 0.01. 0.02. 0.05. 0.1, 0.5, 0.6, 1, 2, 4, 5, 6, 7,8, 9, 10, 20, 50, 80, 90, 100 microns. The term particle is broad andencompasses spheres, drops, whiskers, and irregular shapes. Small sizesof particles help to avoid making thin materials that have breaks or areeasily broken.

Introduction of vehicle may be performed as appropriate to the site ofplacement and use, e.g., by catheter, injection, with adhesives, inminimally invasive surgical processes, during open surgery, and soforth. One method comprises pushing the depot or prosthesis through aneedle with a pusher. For instance, a thin wire with a blunt end sizedto pass into the needle can be used in a syringe with a small diameterinner body so that the thin wire serves the role that a plunger wouldserve in a typical syringe. The term pusher is broad and refers to rods,cylinders, wires, metals, plastics or various other tools or materialsfor forcing a thin depot or prosthesis out of a needle.

Accordingly, the embodiments referring to a first material and a secondmaterial, a plurality of materials, or Material 1 and Material 2, may bechosen independently from the detailed list of materials set forth aboveor from the list of precursor materials provided below.

Anatomy of the Eye

One site for placement of a vehicle, depot or prosthesis for drugdelivery is on, in, or near an eye. The structure of the mammalian eyecan be divided into three main layers or tunics: the fibrous tunic, thevascular tunic, and the nervous tunic. The fibrous tunic, also known asthe tunica fibrosa oculi, is the outer layer of the eyeball consistingof the cornea and sclera. The sclera is the supporting wall of the eyeand gives the eye most of its white color. It is extends from the cornea(the clear front section of the eye) to the optic nerve at the back ofthe eye. The sclera is a fibrous, elastic and protective tissue,composed of tightly packed collagen fibrils, containing about 70% water.

Overlaying the fibrous tunic is the conjunctiva. The conjunctiva is amembrane that covers the sclera (white part of the eye) and lines theinside of the eyelids. The conjunctiva effectively surrounds, covers,and adheres to the sclera. It is has cellular and connective tissue, issomewhat elastic, and can be removed, teased away, or otherwise takendown to expose a surface area of the sclera. The vascular tunic, alsoknown as the tunica vasculosa oculi, is the middle vascularized layerwhich includes the iris, ciliary body, and choroid. The choroid containsblood vessels that supply the retinal cells with oxygen and remove thewaste products of respiration.

The nervous tunic, also known as the tunica nervosa oculi, is the innersensory which includes the retina. The retina contains thephotosensitive rod and cone cells and associated neurons. The retina isa relatively smooth (but curved) layer. It does have two points at whichit is different; the fovea and optic disc. The fovea is a dip in theretina directly opposite the lens, which is densely packed with conecells. The fovea is part of the macula. The fovea is largely responsiblefor color vision in humans, and enables high acuity, which is necessaryin reading. The optic disc is a point on the retina where the opticnerve pierces the retina to connect to the nerve cells on its inside.

The mammalian eye can also be divided into two main segments: theanterior segment and the posterior segment. The anterior segmentconsists of an anterior and posterior chamber. The anterior chamber islocated in front of the iris and posterior to the corneal endotheliumand includes the pupil, iris, ciliary body and aqueous fluid. Theposterior chamber is located posterior to the iris and anterior to thevitreous face where the crystalline lens and zonules fibers arepositioned between an anterior and posterior capsule in an aqueousenvironment.

Light enters the eye, passes through the cornea, and into the first oftwo humors, the aqueous humour. Approximately two-thirds of the totaleyes refractive power comes from the cornea which has a fixed curvature.The aqueous humor is a clear mass which connects the cornea with thelens of the eye, helps maintain the convex shape of the cornea(necessary to the convergence of light at the lens) and provides thecorneal endothelium with nutrients.

The posterior segment is located posterior to the crystalline lens andin front of the retina. It represents approximately two-thirds of theeye that includes the anterior hyaloid membrane and all structuresbehind it: the vitreous humor, retina, and optic nerve. On the otherside of the lens is the second humour, the vitreous humour, which isbounded on all sides: by the lens, ciliary body, suspensory ligamentsand by the retina. It lets light through without refraction, helpsmaintain the shape of the eye and suspends the delicate lens.

FIG. 1 depicts eye 10 having sclera 12, iris 14, pupil 16, and eyelid18. FIG. 2 depicts a perspective view of eye 10 with a partialcross-section that depicts lens 20, inferior oblique muscle 21, medialrectus muscle 23, and optic nerve 25. FIG. 3 is a cross-section of eye10 and depicts cornea 22 that is optically clear and allows light topass iris 14 and penetrate lens 20. Anterior chamber 24 underlies cornea22 and posterior chamber 26 lies between iris 14 and lens 20. Ciliarybody 28 is connected to lens 20. FIG. 3 depicts a portion of theconjunctiva 30, which overlies the sclera 12. The vitreous body 32comprises the jelly-like vitreous humor, with hyaloid canal 34 being inthe same. Fovea 36 is in the macula, retina 38 overlies choroid 37, andthe zonular space is indicated at 42.

Sites for Placement and Use of a Drug Delivery Vehicle

Vehicles may be introduced at various points in, on, or near an eye. Onearea is topically. Another area is intravitreally. In use, for example asyringe, catheter or other device is used to deliver a vehicle,optionally through a needle, into the eye. Drugs or other therapeuticagents are released from the vehicle to the intra-ocular space. Sites ofintroduction include: periocular, canaliculus, punctum, lacrimal canal,on the conjunctiva, on the cornea, on a sclera, inside a sclera, on aninterior wall of the eye, intraocular, invitreal, on a retina, near aretina but not touching a retina, a distance of 1 to 2000 microns from aretina, suprachoroidal, in the choroid, in a potential space, in a lumenartificially (by a user, with a tool) created to receive the depot orprosthesis, in a chamber of an eye, in the posterior chamber, in contactwith vitreous humor, in the hyaline canal, or a combination thereof. Anappropriate device may be chosen to deliver the vehicle, depot orprosthesis depending on the intended site of delivery. Some availabledevices include syringes, catheters, cannulas or trocars, which may havea needle or microneedle, for instance a needle of 27 gauge or smallerinner diameter. The term needle refers to a long, short, micro-length,sharp, or blunt needle and is a broad term that includes metal, plastic,and other materials as may be used on syringes, catheters, cannulas,trocars, and so forth. In some placement methods, a retractor is used tohold back the eyelids, and a user would create a small buttonhole in theconjunctiva about 5-6 mm from the inferior/nasal limbus and dissect theconjunctiva down through Tenon's capsule; to the bare sclera. Then, ablunt cannula (e.g., 15 mm in length) is inserted through the openingand the vehicle, depot or prosthesis is placed. The cannula is removedand the conjunctiva is closed with a cauterization device.

Vehicles may be placed at a site that is a tissue. The term tissue isbroad and includes organs, potential spaces, a tissue compartment, whichis a bodily space filled with fluid or gas, e.g. an eye, ear or otherbody cavity. Shape changing drug delivery vehicle of the various shapes,sizes, effective gauge, aspect ratios, and as otherwise described hereinmay be placed in or on a patient at various sites, e.g. with minimallyinvasive applications or processes through small existing openings orsmall needle holes to create space filling drug delivery depots.Examples of sites are: Vitreous humor or aqueous humor, Canaliculus andampulla, Paranasal sinuses, Joint capsules (e.g. knee, hip, etc.),Lumpectomy site, Biopsy site, Tumor core, Ear canal, Vaginal, Bladder,Esophageal, Bronchial, Abscesses, e.g. Dental, AV malformation sites,Vascular aneurysms or dissections, potential spaces, artificiallycreated spaces or potential spaces, pessary, buccal, anal, uretheral,nasal, breast, iatrogenic, cancer, organs, luminal spaces, naturallumen, vascular, aneurysm.

The vehicles, depots or prostheses may be sized so that, for example,they occupy some or all of the site where they are placed. Thus a sinussite could be partially occupied. In the case of sinus, bronchial, orother sites that can be accessed via tortuous paths, the change of shapeis helpful to make placement or threading through passages feasible, andthe change of shape provides for adequate placement and coverage at theindeed site. The change of shape—to a helix or coil for example,provides a means of securing the depot within the cavity or organ orother site of placement by making the depot too large in cross-sectionto pass through the opening through which it was introduced. Inaddition, the open spaces within said coil or helix provides a route forfluid or gas flow, this leaving normal fluid or gas movement undisturbedor minimally disturbed. Thus, the depot may be used to deliver atherapeutic agent to the cavity or organ or other site where it isdeposited or to downstream tissues where depot-contacting fluid or gascarries the therapeutic agent released from the depot.

The materials described herein may be used to deliver drugs or othertherapeutic agents (e.g., imaging agents or markers) to eyes or tissuesnearby. Some of the disease states are back-of-the-eye diseases. Theterm back-of-the eye disease is recognized by artisans in these fieldsof endeavor and generally refers to any ocular disease of the posteriorsegment that affects the vasculature and integrity of the retina, maculaor choroid leading to visual acuity disturbances, loss of sight orblindness. Disease states of the posterior segment may result from age,trauma, surgical interventions, and hereditary factors. Someback-of-the-eye disease are; age-related macular degeneration (AMD)cystoid macular edema (CME), diabetic macular edema (DME), posterioruveitis, and diabetic retinopathy. Some back-of-the-eye diseases resultfrom unwanted angiogenesis or vascular proliferation, such as maculardegeneration or diabetic retinopathy. Drug treatment options for theseand other conditions are further discussed elsewhere herein.

Examples of downstream delivery are deposition of the depot into aventricle of the brain for delivery of therapeutic agents to thecerebrospinal fluid (CSF), which would distribute the therapeutic agentto brain and spinal tissues without impeding CSF circulation. Anotherexample is deposition into the bronchial system in the lung fordistribution of therapeutic to distal lung tissues without blocking aircirculation. Another example is placement in, at, or near the renalartery to deliver the therapeutic agent to the kidney without impedingblood flow. Another example would be placement in the stomach fordelivery to the stomach or to intestinal sites. Other examples are: in abladder for delivery to the inside of the bladder and/or ureter, withthe material changing shape after placement in the bladder; in a sinusfor delivery and distribution through nasal/sinus areas by flow ofmucus.

Precursor Materials

The materials for the vehicle may be organogel, hydrogels, or xerogels,which, when exposed to aqueous solution, are hydrogels. Hydrogels aremade in aqueous solution and organogels are made in organic solvents.Xerogels are dried organogels or hydrogels. Accordingly, hydrogels andorganogels are made by processes that have many similarities. Hydrogelsand organogels are made from precursors. Precursors are chosen inconsideration of the properties that are desired for the resultantorganogel or hydrogel. There are various suitable precursors for use inmaking the same. The term precursor refers to those moleculescrosslinked to form the hydrogel or organogel matrix. While othermaterials might be present in the hydrogel, such as therapeutic agentsor fillers, they are not precursors. The term matrix is applicable fororganogels, xerogels, and hydrogels. Such matrices include matriceshydratable to have a water content of more than about 20% w/w; Artisanswill immediately appreciate that all ranges and values between theexplicitly stated bounds are contemplated, with any of the followingbeing available as an upper or lower limit: 20%, 99%, 80%, 95%, at least50%, and so forth, with the percentages being w/w and the solvent beingwater for hydrogels. The matrices may be formed by crosslinking watersoluble molecules to form networks of essentially infinite molecularweight. Hydrogels with high water contents are typically soft, pliablematerials. Hydrogels and drug delivery systems as described in U.S.Publication Nos. 2009/0017097, 2011/0142936 and 2012/0071865 may beadapted for use with the materials and methods herein by following theguidance provided herein; these references are hereby incorporatedherein by reference for all purposes and in case of conflict, theinstant specification is controlling.

The matrices may be formed from natural, synthetic, or biosyntheticpolymers. Natural polymers may include glycosminoglycans,polysaccharides, and proteins. Some examples of glycosaminoglycansinclude dermatan sulfate, hyaluronic acid, the chondroitin sulfates,chitin, heparin, keratan sulfate, keratosulfate, and derivativesthereof. In general, the glycosaminoglycans are extracted from a naturalsource and purified and derivatized. However, they also may besynthetically produced or synthesized by modified microorganisms such asbacteria. These materials may be modified synthetically from a naturallysoluble state to a partially soluble or water swellable or hydrogelstate. This modification may be accomplished by various well-knowntechniques, such as by conjugation or replacement of ionizable orhydrogen bondable functional groups such as carboxyl and/or hydroxyl oramine groups with other more hydrophobic groups.

For example, carboxyl groups on hyaluronic acid may be esterified byalcohols to decrease the solubility of the hyaluronic acid. Suchprocesses are used by various manufacturers of hyaluronic acid productsto create hyaluronic acid based sheets, fibers, and fabrics that formhydrogels. Other natural polysaccharides, such as carboxymethylcellulose or oxidized regenerated cellulose, natural gum, agar, agrose,sodium alginate, carrageenan, fucoidan, furcellaran, laminaran, hypnea,eucheuma, gum arabic, gum ghatti, gum karaya, gum tragacanth, locustbeam gum, arbinoglactan, pectin, amylopectin, gelatin, hydrophiliccolloids such as carboxymethyl cellulose gum or alginate gum crosslinkedwith a polyol such as propylene glycol, and the like, also formhydrogels upon contact with aqueous surroundings.

The matrices may be biostable or biodegradable. Examples of biostablehydrophilic polymeric materials are poly(hydroxyalkyl methacrylate),poly(electrolyte complexes), poly(vinylacetate) cross-linked withhydrolysable or otherwise degradable bonds, and water-swellable N-vinyllactams. Other hydrogels include hydrophilic hydrogels known asCARBOPOL®, an acidic carboxy polymer (Carbomer resins are high molecularweight, allylpentaerythritol-crosslinked, acrylic acid-based polymers,modified with C10-C30 alkyl acrylates), polyacrylamides, polyacrylicacid, starch graft copolymers, acrylate polymer, ester cross-linkedpolyglucan. Such hydrogels are described, for example, in U.S. Pat. No.3,640,741 to Etes, U.S. Pat. No. 3,865,108 to Hartop, U.S. Pat. No.3,992,562 to Denzinger et al., U.S. Pat. No. 4,002,173 to Manning etal., U.S. Pat. No. 4,014,335 to Arnold and U.S. Pat. No. 4,207,893 toMichaels, all of which are incorporated herein by reference, with thepresent specification controlling in case of conflict.

The matrices may be made from precursors. The precursors are crosslinkedwith each other. Crosslinks can be formed by covalent bonds or physicalbonds. Examples of physical bonds are ionic bonds, hydrophobicassociation of precursor molecule segments, and crystallization ofprecursor molecule segments. The precursors can be triggered to react toform a crosslinked hydrogel. The precursors can be polymerizable andinclude crosslinkers that are often, but not always, polymerizableprecursors. Polymerizable precursors are thus precursors that havefunctional groups that react with each other to form matrices and/orpolymers made of repeating units. Precursors may be polymers.

Some precursors thus react by chain-growth polymerization, also referredto as addition polymerization, and involve the linking together ofmonomers incorporating double or triple chemical bonds. Theseunsaturated monomers have extra internal bonds which are able to breakand link up with other monomers to form the repeating chain. Monomersare polymerizable molecules with at least one group that reacts withother groups to form a polymer. A macromonomer (or macromer) is apolymer or oligomer that has at least one reactive group, often at theend, which enables it to act as a monomer; each macromonomer molecule isattached to the polymer by reaction the reactive group. Thusmacromonomers with two or more monomers or other functional groups tendto form covalent crosslinks. Addition polymerization is involved in themanufacture of, e.g., polypropylene or polyvinyl chloride. One type ofaddition polymerization is living polymerization.

Some precursors thus react by condensation polymerization that occurswhen monomers bond together through condensation reactions. Typicallythese reactions can be achieved through reacting molecules incorporatingalcohol, amine or carboxylic acid (or other carboxyl derivative)functional groups. When an amine reacts with a carboxylic acid an amideor peptide bond is formed, with the release of water. Some condensationreactions follow a nucleophilic acyl substitution, e.g., as in U.S. Pat.No. 6,958,212, which is hereby incorporated by reference herein in itsentirety to the extent it does not contradict what is explicitlydisclosed herein. Some precursors react by a chain growth mechanism.Chain growth polymers are defined as polymers formed by the reaction ofmonomers or macromonomers with a reactive center. A reactive center is aparticular location within a chemical compound that is the initiator ofa reaction in which the chemical is involved. In chain-growth polymerchemistry, this is also the point of propagation for a growing chain.The reactive center is commonly radical, anionic, or cationic in nature,but can also take other forms. Chain growth systems include free radicalpolymerization, which involves a process of initiation, propagation andtermination. Initiation is the creation of free radicals necessary forpropagation, as created from radical initiators, e.g., organic peroxidemolecules. Termination occurs when a radical reacts in a way thatprevents further propagation. The most common method of termination isby coupling where two radical species react with each other forming asingle molecule. Some precursors react by a step growth mechanism, andare polymers formed by the stepwise reaction between functional groupsof monomers. Most step growth polymers are also classified ascondensation polymers, but not all step growth polymers releasecondensates. Monomers may be polymers or small molecules. A polymer is ahigh molecular weight molecule formed by combining many smallermolecules (monomers) in a regular pattern. Oligomers are polymers havingless than about 20 monomeric repeat units. A small molecule generallyrefers to a molecule that is less than about 2000 Daltons. Theprecursors may thus be small molecules, such as acrylic acid or vinylcaprolactam, larger molecules containing polymerizable groups, such asacrylate-capped polyethylene glycol (PEG-diacrylate), or other polymerscontaining ethylenically-unsaturated groups, such as those of U.S. Pat.No. 4,938,763 to Dunn et al, U.S. Pat. Nos. 5,100,992 and 4,826,945 toCohn et al, or U.S. Pat. Nos. 4,741,872 and 5,160,745 to DeLuca et al.,each of which is hereby incorporated by reference herein in its entiretyto the extent it does not contradict what is explicitly disclosedherein.

To form covalently crosslinked matrices, the precursors must becovalently crosslinked together. In general, polymeric precursors arepolymers that will be joined to other polymeric precursors at two ormore points, with each point being a linkage to the same or differentpolymers. Precursors with at least two reactive centers (for example, infree radical polymerization) can serve as crosslinkers since eachreactive group can participate in the formation of a different growingpolymer chain. In the case of functional groups without a reactivecenter, among others, crosslinking requires three or more suchfunctional groups on at least one of the precursor types. For instance,many electrophilic-nucleophilic reactions consume the electrophilic andnucleophilic functional groups so that a third functional group isneeded for the precursor to form a crosslink. Such precursors thus mayhave three or more functional groups and may be crosslinked byprecursors with two or more functional groups. A crosslinked moleculemay be crosslinked via an ionic or covalent bond, a physical force, orother attraction. A covalent crosslink, however, will typically offerstability and predictability in reactant product architecture.

In some embodiments, each precursor is multifunctional, meaning that itcomprises two or more electrophilic or nucleophilic functional groups,such that a nucleophilic functional group on one precursor may reactwith an electrophilic functional group on another precursor to form acovalent bond. At least one of the precursors comprises more than twofunctional groups, so that, as a result of electrophilic-nucleophilicreactions, the precursors combine to form crosslinked polymericproducts.

The precursors may have biologically inert and hydrophilic portions,e.g., a core. In the case of a branched polymer, a core refers to acontiguous portion of a molecule joined to arms that extend from thecore, with the arms having a functional group, which is often at theterminus of the branch. A hydrophilic molecule, e.g., a precursor orprecursor portion, has a solubility of at least 1 g/100 mL in an aqueoussolution. A hydrophilic portion may be, for instance, a polyether, forexample, polyalkylene oxides such as polyethylene glycol (PEG),polyethylene oxide (PEO), polyethylene oxide-co-polypropylene oxide(PPO), co-polyethylene oxide block or random copolymers, and polyvinylalcohol (PVA), poly (vinyl pyrrolidinone) (PVP), poly (amino acids,dextran, or a protein. The precursors may have a polyalkylene glycolportion and may be polyethylene glycol based, with at least about 80% or90% by weight of the polymer comprising polyethylene oxide repeats. Thepolyethers and more particularly poly (oxyalkylenes) or poly (ethyleneglycol) or polyethylene glycol are generally hydrophilic. As iscustomary in these arts, the term PEG is used to refer to PEO with orwithout hydroxyl end groups.

A precursor may also be a macromolecule (or macromer), which is amolecule having a molecular weight in the range of a thousand to manymillions. The hydrogel may be made with at least one of the precursorsas a small molecule of about 1000 Da or less (alternatively: 2000 Da orless). The macromolecule, when reacted in combination with a smallmolecule (of about 1000 Da or less/200 Da or less), is preferably atleast five to fifty times greater in molecular weight than the smallmolecule and is preferably less than about 60,000 Da; artisans willimmediately appreciate that all the ranges and values within theexplicitly stated ranges are contemplated. A more preferred range is amacromolecule that is about seven to about thirty times greater inmolecular weight than the crosslinker and a most preferred range isabout ten to twenty times difference in weight. Further, amacromolecular molecular weight of 5,000 to 50,000 is useful, as is amolecular weight of 7,000 to 40,000 or a molecular weight of 10,000 to20,000. There are certain advantage to having a small molecule, such asdiffusivity for completion of reactions.

Certain macromeric precursors are the crosslinkable, biodegradable,water-soluble macromers described in U.S. Pat. No. 5,410,016 to Hubbellet al, which is hereby incorporated herein by reference in its entiretyto the extent it does not contradict what is explicitly disclosed. Thesemacromers are characterized by having at least two polymerizable groups,separated by at least one degradable region.

Synthetic precursors may be used. Synthetic refers to a molecule notfound in nature or not normally found in a human. Some syntheticprecursors are free of amino acids or free of amino acid sequences thatoccur in nature. Some synthetic precursors are polypeptides that are notfound in nature or are not normally found in a human body, e.g., di-,tri-, or tetra-lysine. Some synthetic molecules have amino acid residuesbut only have one, two, or three that are contiguous, with the aminoacids or clusters thereof being separated by non-natural polymers orgroups. Polysaccharides or their derivatives are thus not synthetic.

Alternatively, natural proteins or polysaccharides may be adapted foruse with these methods, e.g., collagens, fibrin(ogen)s, albumins,alginates, hyaluronic acid, and heparins. These natural molecules mayfurther include chemical derivitization, e.g., synthetic polymerdecorations. The natural molecule may be crosslinked via its nativenucleophiles or after it is derivatized with functional groups, e.g., asin U.S. Pat. Nos. 5,304,595, 5,324,775, 6,371,975, and 7,129,210, eachof which is hereby incorporated by reference to the extent it does notcontradict what is explicitly disclosed herein. Natural refers to amolecule found in nature. Natural polymers, for example proteins orglycosaminoglycans, e.g., collagen, fibrinogen, albumin, and fibrin, maybe crosslinked using reactive precursor species with electrophilicfunctional groups. Natural polymers normally found in the body areproteolytically degraded by proteases present in the body. Such polymersmay be reacted via functional groups such as amines, thiols, orcarboxyls on their amino acids or derivatized to have activatablefunctional groups. While natural polymers may be used in hydrogels,their time to gelation and ultimate mechanical properties must becontrolled by appropriate introduction of additional functional groupsand selection of suitable reaction conditions, e.g., pH.

Precursors may be made with a hydrophobic portion provided that theresultant hydrogel retains the requisite amount of water, e.g., at leastabout 20%. In some cases, the precursor is nonetheless soluble in waterbecause it also has a hydrophilic portion. In other cases, the precursormakes dispersion in the water (a suspension) but is nonethelessreactable to from a crosslinked material. Some hydrophobic portions mayinclude a plurality of alkyls, polypropylenes, alkyl chains, or othergroups. Some precursors with hydrophobic portions are sold under thetrade names PLURONIC F68, JEFFAMINE, or TETRONIC. A hydrophobic moleculeor a hydrophobic portion of a copolymer or the like is one that issufficiently hydrophobic to cause the molecule (e.g., polymer orcopolymer) to aggregate to form micelles or microphases involving thehydrophobic domains in an aqueous continuous phase or one that, whentested by itself, is sufficiently hydrophobic to precipitate from, orotherwise change phase while within, an aqueous solution of water at pHfrom about 7 to about 7.5 at temperatures from about 30 to about 50degrees Centigrade. Embodiments of the invention include choosing alow-solubility agent and choosing a precursor that comprises hydrophobicand hydrophilic portions. The hydrophobic/hydrophilic precursor maycomprise one or more functional groups: nucleophiles or electrophiles.The hydrophilic portion, the hydrophobic portion, or both, may be chosento receive such functional groups. Examples of such agents are, ingeneral, TKIs. Low-solubility means no more than 200 μg/ml soluble inwater, the water being pure water, and the drug being essentially pureor a salt. Artisans will immediately appreciate that all ranges andvalues between the explicitly stated bounds are contemplated, with anyof the following being available as an upper or lower limit: 200, 150,100, 50, 25, 20, e.g., less than 100 or less than 50 μg/ml soluble inwater.

Precursors may have, e.g., 2-100 arms, with each arm having a terminus,bearing in mind that some precursors may be dendrimers or other highlybranched materials. An arm on a hydrogel precursor refers to a linearchain of chemical groups that connect a crosslinkable functional groupto a polymer core. Some embodiments are precursors with between 3 and300 arms; artisans will immediately appreciate that all the ranges andvalues within the explicitly stated ranges are contemplated, e.g., 4 to16, 8 to 100, or at least 6 arms.

The matrices can be made, e.g., from a multi-armed precursor with afirst set of functional groups and a low molecular-weight precursorhaving a second set of functional groups. For example, a six-armed oreight-armed precursor may have hydrophilic arms, e.g., polyethyleneglycol, terminated with primary amines, with the molecular weight of thearms being about 1,000 to about 40,000; artisans will immediatelyappreciate that all ranges and values within the explicitly statedbounds are contemplated. Such precursors may be mixed with relativelysmaller precursors, for example, molecules with a molecular weight ofbetween about 100 and about 5000, or no more than about 800, 1000, 2000,or 5000 having at least about three functional groups, or between about3 to about 16 functional groups; ordinary artisans will appreciate thatall ranges and values between these explicitly articulated values arecontemplated. Such small molecules may be polymers or non-polymers andnatural or synthetic.

Precursors that are not dendrimers may be used. Dendritic molecules arehighly branched radially symmetrical polymers in which the atoms arearranged in many arms and subarms radiating out from a central core.Dendrimers are characterized by their degree of structural perfection asbased on the evaluation of both symmetry and polydispersity and requireparticular chemical processes to synthesize. Accordingly, an artisan canreadily distinguish dendrimer precursors from non-dendrimer precursors.Dendrimers have a shape that is typically dependent on the solubility ofits component polymers in a given environment, and can changesubstantially according to the solvent or solutes around it, e.g.,changes in temperature, pH, or ion content.

Precursors may be dendrimers, e.g., as in U.S. Publication Nos.2004/0086479 and 2004/0131582 and PCT Publication Nos. WO07005249,WO07001926 and WO06031358, or the U.S. counterparts thereof; dendrimersmay also be useful as multifunctional precursors, e.g., as in U.S.Publication Nos. 2004/0131582 and 2004/0086479 and PCT Publication Nos.WO06031388 and WO06031388; each of which US and PCT applications arehereby incorporated by reference herein in its entirety to the extentthey do not contradict what is explicitly disclosed herein. Dendrimersare highly ordered possess high surface area to volume ratios, andexhibit numerous end groups for potential functionalization. Embodimentsinclude multifunctional precursors that are not dendrimers.

Some embodiments include a precursor that consists essentially of anoligopeptide sequence of no more than five residues, e.g., amino acidscomprising at least one amine, thiol, carboxyl, or hydroxyl side chain.A residue is an amino acid, either as occurring in nature or derivatizedthereof. The backbone of such an oligopeptide may be natural orsynthetic. In some embodiments, peptides of two or more amino acids arecombined with a synthetic backbone to make a precursor; certainembodiments of such precursors have a molecular weight in the range ofabout 100 to about 10,000 or about 300 to about 500 Artisans willimmediately appreciate that all ranges and values between theseexplicitly articulated bounds are contemplated.

Precursors may be prepared to be free of amino acid sequences cleavableby enzymes present at the site of introduction, including free ofsequences susceptible to attach by metalloproteinases and/orcollagenases. Further, precursors may be made to be free of all aminoacids, or free of amino acid sequences of more than about 50, 30, 20,10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acids. Precursors may benon-proteins, meaning that they are not a naturally occurring proteinand cannot be made by cleaving a naturally occurring protein and cannotbe made by adding synthetic materials to a protein. Precursors may benon-collagen, non-fibrin, non-fibrinogen, and non-albumin, meaning thatthey are not one of these proteins and are not chemical derivatives ofone of these proteins. The use of non-protein precursors and limited useof amino acid sequences can be helpful for avoiding immune reactions,avoiding unwanted cell recognition, and avoiding the hazards associatedwith using proteins derived from natural sources. Precursors can also benon-saccharides (free of saccharides) or essentially non-saccharides(free of more than about 5% saccharides by w/w of the precursormolecular weight. Thus a precursor may, for example, exclude hyaluronicacid, heparin, or gellan. Precursors can also be both non-proteins andnon-saccharides.

Peptides may be used as precursors. In general, peptides with less thanabout 10 residues are preferred, although larger sequences (e.g.,proteins) may be used. Artisans will immediately appreciate that everyrange and value within these explicit bounds is included, e.g., 1-10,2-9, 3-10, 1, 2, 3, 4, 5, 6, or 7. Some amino acids have nucleophilicgroups (e.g., primary amines or thiols) or groups that can bederivatized as needed to incorporate nucleophilic groups orelectrophilic groups (e.g., carboxyls or hydroxyls). Polyamino acidpolymers generated synthetically are normally considered to be syntheticif they are not found in nature and are engineered not to be identicalto naturally occurring biomolecules.

Some matrices are made with a polyethylene glycol-containing precursor.Polyethylene glycol (PEG, also referred to as polyethylene oxide whenoccurring in a high molecular weight) refers to a polymer with a repeatgroup (CH₂CH₂O)_(n), with n being at least 3. A polymeric precursorhaving a polyethylene glycol thus has at least three of these repeatgroups connected to each other in a linear series. The polyethyleneglycol content of a polymer or arm is calculated by adding up all of thepolyethylene glycol groups on the polymer or arm, even if they areinterrupted by other groups. Thus, an arm having at least 1000 MWpolyethylene glycol has enough CH₂CH₂O groups to total at least 1000 MW.As is customary terminology in these arts, a polyethylene glycol polymerdoes not necessarily refer to a molecule that terminates in a hydroxylgroup. Molecular weights are abbreviated in thousands using the symbolk, e.g., with 15K meaning 15,000 molecular weight, i.e., 15,000 Daltons.NH2 refers to an amine termination. SG refers to succinimidyl glutarate.SS refers to succinimidyl succinate. SAP refers to succinimidyl adipate.SAZ refers to succinimidyl azelate. SS, SG, SAP and SAZ are succinimidylesters that have an ester group that degrades by hydrolysis in water.Hydrolytically degradable or water-degradable thus refers to a materialthat would spontaneously degrade in vitro in an excess of water withoutany enzymes or cells present to mediate the degradation. A time fordegradation refers to effective disappearance of the material as judgedby the naked eye. Trilysine (also abbreviated LLL) is a synthetictripeptide. PEG and/or hydrogels, as well as compositions that comprisethe same, may be provided in a form that is pharmaceutically acceptable,meaning that it is highly purified and free of contaminants, e.g.,pyrogens.

Hydrogel Structures

The hydrogel's structure and the material composition of the hydrogel'sprecursors determine its properties. Precursor factors includeproperties such as biocompatibility, water solubility, hydrophilicity,molecular weight, arm length, number of arms, functional groups,distance between crosslinks, degradability, and the like. The choice ofreaction conditions (as a hydrogel or organogel, choice of buffers, pH,precursors, and so forth) also effects the hydrogel's structure andproperties, including choices of solvents, reaction schemes, reactantconcentrations, solids content, and the like. There can be a variety ofways to achieve certain properties, or combination of properties. On theother hand some properties are in tension with each other, for instancebrittleness may increase as a distance between crosslinks or solidscontent increases. Strength may be increased by increasing the number ofcrosslinks but swelling may thereby be reduced. Artisans will appreciatethat the same materials may be used to make matrices with a great rangeof structures that will have highly distinct mechanical properties andperformance, such that the achievement of a particular property shouldnot be merely assumed based on the general types of precursors that areinvolved.

The spacing between molecular strands of the hydrogel (the matrix)affects several hydrogel properties, including a rate of diffusion ofmolecules. The crosslinking density can be controlled by the choice ofthe overall molecular weight of the precursor(s) used as crosslinker(s)and other precursor(s) and the number of functional groups available perprecursor molecule. A lower molecular weight between crosslinks such as200 will give much higher crosslinking density as compared to a highermolecular weight between crosslinks such as 500,000; artisans willimmediately appreciate that all ranges and values within this range arecontemplated and supported, e.g., 200 to 250,000, 500 to 400,000, 5,000,10,000, 20,000, 30,000, 40,000, 50,000, 60,000, 70,000, 80,000, 90,000,100,000, and so forth. The crosslinking density also may be controlledby the overall percent solids of the crosslinker and functional polymersolutions. Yet another method to control crosslink density is byadjusting the stoichiometry of nucleophilic functional groups toelectrophilic functional groups. A one to one ratio leads to the highestcrosslink density. Precursors with longer distances betweencrosslinkable sites form gels that are generally softer, more compliant,and more elastic. Thus an increased length of a water-soluble segment,such as a polyethylene glycol, tends to enhance elasticity to producedesirable physical properties. Thus certain embodiments are directed toprecursors with water soluble segments having molecular weights in therange of 2,000 to 100,000; artisans will immediately appreciate that allthe ranges and values within the explicitly stated ranges arecontemplated, e.g. 5,000 to 35,000. The solids content of the hydrogelcan affect its mechanical properties and biocompatibility and reflects abalance between competing requirements. A relatively low solids contentis useful, e.g., between about 2.5% to about 20%, including all rangesand values there between, e.g., about 2.5% to about 10%, about 5% toabout 15%, or less than about 15%.

Reaction kinetics are generally controlled in light of the particularfunctional groups unless an external initiator or chain transfer agentis required, in which case triggering the initiator or manipulating thetransfer agent can be a controlling step. In some embodiments, themolecular weights of the precursors are used to affect reaction times.Precursors with lower molecular weights tend to speed the reaction, sothat some embodiments have at least one precursor with a molecularweight of at least 5,000 to 50,000 or 150,000 Daltons. Preferably thecrosslinking reaction leading to gelation occurs within about 2 to about10 or to about 30 minutes; artisans will immediately appreciate that allthe ranges and values within the explicitly stated ranges arecontemplated, e.g., at least 120 seconds, or between 180 to 600 seconds.Gelation time is measured by applying the precursors to a flat surfaceand determining the time at which there is substantially no flow downthe surface when it is titled at an angle of about 60 degrees (i.e., asteep angle, close to perpendicular).

The matrices may be low-swelling, as measurable by the hydrogel having aweight increasing no more than about 0% to about 10% or to about 50%upon exposure to a physiological solution for twenty-four hours relativeto a weight of the hydrogel at the time of formation. One embodiment forreducing swelling is to increase the number of crosslinks, bearing inmind, however, that crosslinks can increase rigidity or brittleness.Another embodiment is to reduce the average chain distance betweencrosslinks. Another embodiment is to use precursors with many arms, asexplained below. Another embodiment to reduce swelling is to control thedegree of hydrophilicity, with less hydrophilic materials tending toswell less; for instance, highly hydrophilic materials such as PEOs canbe combined with less hydrophilic materials such as PPO or evenhydrophobic groups such as alkyls.

Another embodiment to reduce or control swelling is to choose precursorsthat have a high degree of solvation at the time of crosslinking butsubsequently become less solvated and having a radius of solvation thateffectively shrinks; in other words, the precursor is spread-out insolution when crosslinked but later contracts. Changes to pH,temperature, solids concentration, and solvent environment can causesuch changes; moreover, an increase in the number of branches (withother factors being held effectively constant) will tend to also havethis effect. The number of arms are believed to sterically hinder eachother so that they spread-out before crosslinking, but these stericeffects are offset by other factors after polymerization. In someembodiments, precursors have a plurality of similar charges so as toachieve these effects, e.g., a plurality of functional groups having anegative charge, or a plurality of arms each having a positive charge,or each arm having a functional group of similar charges beforecrosslinking or other reaction.

Hydrogels described herein can include hydrogels that swell minimallyafter deposition. Such medical low-swellable hydrogels may have a weightupon polymerization that increases no more than, e.g., about 50%, about10%, about 5%, about 0% by weight upon exposure to a physiologicalsolution, or that shrink (decrease in weight and volume), e.g., by atleast about 5%, at least about 10%, or more. Artisans will immediatelyappreciate that all ranges and values within or otherwise relating tothese explicitly articulated limits are disclosed herein. Unlessotherwise indicated, swelling of a hydrogel relates to its change involume (or weight) between the time of its formation when crosslinkingis effectively complete and the time after being placed in vitro aphysiological solution in an unconstrained state for twenty-four hours,at which point it may be reasonably assumed to have achieved itsequilibrium swelling state. % swelling=[(Weight at equilibriumswelling−Weight at initial formation)/Weight at initial formation]*100.The weight of the hydrogel includes the weight of the solution in thehydrogel.

Functional Groups

The precursors for covalent crosslinking have functional groups thatreact with each other to form the material via covalent bonds, eitheroutside a patient, or in situ. The functional groups generally arepolymerizable, a broad category that encompasses free radical, addition,and condensation polymerization and also groups forelectrophile-nucleophile reactions. Various aspects of polymerizationreactions are discussed in the precursors section herein.

Thus in some embodiments, precursors have a polymerizable group that isactivated by photoinitiation or redox systems as used in thepolymerization arts, or electrophilic functional groups, for instance:carbodiimidazole, sulfonyl chloride, chlorocarbonates,N-hydroxysuccinimidyl ester, succinimidyl ester or sulfasuccinimidylesters, or as in U.S. Pat. Nos. 5,410,016 or 6,149,931, each of whichare hereby incorporated by reference herein in its entirety to theextent they do not contradict what is explicitly disclosed herein. Thenucleophilic functional groups may be, for example, amine, hydroxyl,carboxyl, and thiol. Another class of electrophiles are acyls, e.g., asin U.S. Pat. No. 6,958,212, which describes, among other things, Michaeladdition schemes for reacting polymers.

Certain functional groups, such as alcohols or carboxylic acids, do notnormally react with other functional groups, such as amines, underphysiological conditions (e.g., pH 7.2-11.0, 37° C.). However, suchfunctional groups can be made more reactive by using an activating groupsuch as N-hydroxysuccinimide. Certain activating groups includecarbonyldiimidazole, sulfonyl chloride, aryl halides, sulfosuccinimidylesters, N-hydroxysuccinimidyl ester, succinimidyl ester, epoxide,aldehyde, maleimides, imidoesters and the like. The N-hydroxysuccinimideesters or N-hydroxysulfosuccinimide (NHS) groups are useful groups forcrosslinking of proteins or amine-containing polymers, e.g., aminoterminated polyethylene glycol. An advantage of an NHS-amine reaction isthat the reaction kinetics are favorable, but the gelation rate may beadjusted through pH or concentration. The NHS-amine crosslinkingreaction leads to formation of N-hydroxysuccinimide as a side product.Sulfonated or ethoxylated forms of N-hydroxysuccinimide have arelatively increased solubility in water and hence their rapid clearancefrom the body. An NHS-amine crosslinking reaction may be carried out inaqueous solutions and in the presence of buffers, e.g., phosphate buffer(pH 5.0-7.5), triethanolamine buffer (pH 7.5-9.0), or borate buffer (pH9.0-12), or sodium bicarbonate buffer (pH 9.0-10.0). Aqueous solutionsof NHS based crosslinkers and functional polymers preferably are madejust before the crosslinking reaction due to reaction of NHS groups withwater. The reaction rate of these groups may be delayed by keeping thesesolutions at lower pH (pH 4-7). Buffers may also be included in thehydrogels introduced into a body.

In some embodiments, each precursor comprises only nucleophilic or onlyelectrophilic functional groups, so long as both nucleophilic andelectrophilic precursors are used in the crosslinking reaction. Thus,for example, if a crosslinker has nucleophilic functional groups such asamines, the functional polymer may have electrophilic functional groupssuch as N-hydroxysuccinimides. On the other hand, if a crosslinker haselectrophilic functional groups such as sulfosuccinimides, then thefunctional polymer may have nucleophilic functional groups such asamines or thiols. Thus, functional polymers such as proteins, poly(allylamine), or amine-terminated di- or multifunctional poly(ethylene glycol)can be used.

One embodiment has reactive precursor species with 2 to 16 nucleophilicfunctional groups each and reactive precursor species with 2 to 16electrophilic functional groups each; artisans will immediatelyappreciate that all the ranges and values within the explicitly statedranges are contemplated, for instance 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 13, 14, 15, or 16 groups.

The functional groups may be, e.g., electrophiles reactable withnucleophiles, groups reactable with specific nucleophiles, e.g., primaryamines, groups that form amide bonds with materials in the biologicalfluids, groups that form amide bonds with carboxyls, activated-acidfunctional groups, or a combination of the same. The functional groupsmay be, e.g., a strong electrophilic functional group, meaning anelectrophilic functional group that effectively forms a covalent bondwith a primary amine in aqueous solution at pH 9.0 at room temperatureand pressure and/or an electrophilic group that reacts by a ofMichael-type reaction. The strong electrophile may be of a type thatdoes not participate in a Michaels-type reaction or of a type thatparticipates in a Michaels-type reaction.

A Michael-type reaction refers to the 1, 4 addition reaction of anucleophile on a conjugate unsaturated system. The addition mechanismcould be purely polar, or proceed through a radical-like intermediatestate(s); Lewis acids or appropriately designed hydrogen bonding speciescan act as catalysts. The term conjugation can refer both to alternationof carbon-carbon, carbon-heteroatom or heteroatom-heteroatom multiplebonds with single bonds, or to the linking of a functional group to amacromolecule, such as a synthetic polymer or a protein. Michael-typereactions are discussed in detail in U.S. Pat. No. 6,958,212, which ishereby incorporated by reference herein in its entirety for all purposesto the extent it does not contradict what is explicitly disclosedherein.

Examples of strong electrophiles that do not participate in aMichaels-type reaction are: succinimides, succinimidyl esters, orNHS-esters. Examples of Michael-type electrophiles are acrylates,methacrylates, methylmethacrylates, and other unsaturated polymerizablegroups.

Initiating Systems

Some precursors react using initiators. An initiator group is a chemicalgroup capable of initiating a free radical polymerization reaction. Forinstance, it may be present as a separate component, or as a pendentgroup on a precursor. Initiator groups include thermal initiators,photoactivatable initiators, and oxidation-reduction (redox) systems.Long wave UV and visible light photoactivatable initiators include, forexample, ethyl eosin groups, 2, 2-dimethoxy-2-phenyl acetophenonegroups, other acetophenone derivatives, thioxanthone groups,benzophenone groups, and camphorquinone groups. Examples of thermallyreactive initiators include 4, 4′ azobis (4-cyanopentanoic acid) groups,and analogs of benzoyl peroxide groups. Several commercially availablelow temperature free radical initiators, such as V-044, available fromWako Chemicals USA, Inc., Richmond, Va., may be used to initiate freeradical crosslinking reactions at body temperatures to form hydrogelcoatings with the aforementioned monomers.

Metal ions may be used either as an oxidizer or a reductant in redoxinitiating systems. For example, ferrous ions may be used in combinationwith a peroxide or hydroperoxide to initiate polymerization, or as partsof a polymerization system. In this case, the ferrous ions would serveas a reductant. Alternatively, metal ions may serve as an oxidant. Forexample, the ceric ion (4+ valence state of cerium) interacts withvarious organic groups, including carboxylic acids and urethanes, toremove an electron to the metal ion, and leave an initiating radicalbehind on the organic group. In such a system, the metal ion acts as anoxidizer. Potentially suitable metal ions for either role are any of thetransition metal ions, lanthanides and actinides, which have at leasttwo readily accessible oxidation states. Particularly useful metal ionshave at least two states separated by only one difference in charge. Ofthese, the most commonly used are ferric/ferrous; cupric/cuprous;ceric/cerous; cobaltic/cobaltous; vanadate V vs. IV; permanganate; andmanganic/manganous. Peroxygen containing compounds, such as peroxidesand hydroperoxides, including hydrogen peroxide, t-butyl hydroperoxide,t-butyl peroxide, benzoyl peroxide, cumyl peroxide may be used.

An example of an initiating system is the combination of a peroxygencompound in one solution, and a reactive ion, such as a transitionmetal, in another. In this case, no external initiators ofpolymerization are needed and polymerization proceeds spontaneously andwithout application of external energy or use of an external energysource when two complementary reactive functional groups containingmoieties interact at the application site.

Visualization Agents

A visualization agent may be used in a xerogel/organogel/hydrogel; itreflects or emits light at a wavelength detectable to a human eye sothat a user applying the hydrogel could observe the object when itcontains an effective amount of the agent. Agents that require a machineaid for imaging are referred to as imaging agents herein, and examplesinclude: radioopaque contrast agents and ultrasound contrast agents.Some biocompatible visualization agents are FD & C BLUE #1, FD & C BLUE#2, and methylene blue. These agents, if used, are preferably present inthe final electrophilic-nucleophilic reactive precursor species mix at aconcentration of more than 0.05 mg/ml and preferably in a concentrationrange of at least 0.1 to about 12 mg/ml, and more preferably in therange of 0.1 to 4.0 mg/ml, although greater concentrations maypotentially be used, up to the limit of solubility of the visualizationagent. Visualization agents may be covalently linked to the molecularnetwork of the xerogel/hydrogel, thus preserving visualization afterapplication to a patient until the hydrogel hydrolyzes to dissolution.Visualization agents may be selected from among any of the variousnon-toxic colored substances suitable for use in medical implantablemedical devices, such as FD & C BLUE dyes 3 and 6, eosin, methyleneblue, indocyanine green, or colored dyes normally found in syntheticsurgical sutures. Reactive visualization agents such as NHS-fluoresceincan be used to incorporate the visualization agent into the molecularnetwork of the xerogel/hydrogel. The visualization agent may be presentwith either reactive precursor species, e.g., a crosslinker orfunctional polymer solution. The preferred colored substance may or maynot become chemically bound to the hydrogel.

Biodegradation

An hydrogel may be formed so that, upon hydration in physiologicalsolution, a hydrogel is formed that is water-degradable, as measurableby the hydrogel losing its mechanical strength and eventuallydissipating in vitro in an excess of water by hydrolytic degradation ofwater-degradable groups. This test is predictive ofhydrolytically-driven dissolution in vivo, a process that is in contrastto cell or protease-driven degradation. Significantly, however,polyanhydrides or other conventionally-used degradable materials thatdegrade to acidic components tend to cause inflammation in tissues. Thehydrogels, however, may exclude such materials, and may be free ofpolyanhydrides, anhydride bonds, and/or free of precursors that degradeinto acid or diacids, and/or free of PLA, PLGA, PLA/PLGA.

For example, electrophilic groups such as SG (N-hydroxysuccinimidylglutarate), SS (N-hydroxysuccinimidyl succinate), SC(N-hydroxysuccinimidyl carbonate), SAP (N-hydroxysuccinimidyl adipate)or SAZ (N-hydroxysuccinimidyl azelate) may be used and have estericlinkages that are hydrolytically labile. More linear hydrophobiclinkages such as pimelate, suberate, azelate or sebacate linkages mayalso be used, with these linkages being less degradable than succinate,glutarate or adipate linkages. Branched, cyclic or other hydrophobiclinkages may also be used. Polyethylene glycols and other precursors maybe prepared with these groups. The crosslinked hydrogel degradation mayproceed by the water-driven hydrolysis of the biodegradable segment whenwater-degradable materials are used. Polymers that include esterlinkages may also be included to provide a desired degradation rate,with groups being added or subtracted near the esters to increase ordecrease the rate of degradation. Thus it is possible to construct ahydrogel with a desired degradation profile, from a few days to manymonths, using a degradable segment. If polyglycolate is used as thebiodegradable segment, for instance, a crosslinked polymer could be madeto degrade in about 1 to about 30 days depending on the crosslinkingdensity of the network. Similarly, a polycaprolactone based crosslinkednetwork can be made to degrade in about 1 to about 8 months. Thedegradation time generally varies according to the type of degradablesegment used, in the following order:polyglycolate<polylactate<polytrimethylene carbonate<polycaprolactone.Thus it is possible to construct a hydrogel with a desired degradationprofile, from a few days to many months, using a degradable segment.Some embodiments include precursors that are free of adjacent estergroups and/or have no more than one ester group per arm on one or moreof the precursors: control of the number and position of the esters canassist in uniform degradation of the hydrogel.

A biodegradable linkage in the organogel and/or xerogel and/or hydrogeland/or precursor may be water-degradable or enzymatically degradable.Illustrative water-degradable biodegradable linkages include polymers,copolymers and oligomers of glycolide, dl-lactide, 1-lactide, dioxanone,esters, carbonates, and trimethylene carbonate. Illustrativeenzymatically biodegradable linkages include peptidic linkages cleavableby metalloproteinases and collagenases. Examples of biodegradablelinkages include polymers and copolymers of poly(hydroxy acid)s,poly(orthocarbonate)s, poly(anhydride)s, poly(lactone)s,poly(aminoacid)s, poly(carbonate)s, and poly(phosphonate)s.

If it is desired that a biocompatible crosslinked matrix bebiodegradable or absorbable, one or more precursors having biodegradablelinkages (or just one biodegradable linkage, for example an ester)present in between the functional groups may be used. The biodegradablelinkage optionally also may serve as the water soluble core of one ormore of the precursors used to make the matrix. For each approach,biodegradable linkages may be chosen such that the resultingbiodegradable biocompatible crosslinked polymer will degrade or beabsorbed in a desired period of time.

Bipolymeric vehicles may be chosen with hydrogels having different ratesof degradation. The materials have a plurality of hydrogels in layers,e.g., one or more inner hydrogels with a layer of an outer hydrogel onthem. For instance, one or more rods arranged in parallel or as strands(twisted, braided) inside a hydrogel layer. The various hydrogels may bechosen to have different degradation rates. Degradation of an interiorhydrogel can be advantageous to accelerate relative to another innerhydrogel or outer hydrogel to provide for a greater surface area of thedrug, provided, however, that its degradation does not cause the otherlayer to lose a curved shape that is desired to avoid harm to sensitivetissues. Delay of degradation of an inner hydrogel relative to otherhydrogels can be advantageous to maintain a curved shape, e.g., to keepan intraocular vehicle coiled or in a compact shape, until some or allof the other layers degrade. Accordingly one of, or a plurality of,inner hydrogels can be independently chosen to have a degradation thatis greater than, or less than, other hydrogels and/or an outermosthydrogel layer. Thus one or more differential degradation rates mayprovide for the vehicle to maintain an initial shape (e.g., coil shape)for a period of time between 1-365 days (all ranges contemplated: 1, 2,7, 14, 21, 30 days, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months). Thisproperty provides for the shape to be maintained until advanced stagesof the degradation process. And the differential degradation rates maybe used to determine the ability to unfurl the coil or other compactshape at particular stages of the degradation process. Moreover, in thecase wherein multiple hydrogels/rods/strands are surrounded by a secondmaterial, they may be independently selected to have a rangecoefficients of elongation or swelling such that complex shape changesupon exposure to physiological fluid can be engineered. The variousrates may be controlled by hydrolytic and/or enzymatic degradation timesto control shape changes during the degradation process.

Drugs or Other Therapeutic Agents for Delivery

Therapeutic agents are known for many purposes. These include, forexample, agents for treating conditions that may result frominflammatory or abnormal vascular conditions, retinal vein occlusion,geographic atrophy, retinitis pigmentosa, retinoblastoma, etc. Forcancer, agents may be, e.g., anti-cancer drugs, anti-VEGFs, or drugsknown for use in cancer treatment.

Therapeutic agents may be those that are, e.g., antiangiogenic,anti-VEGF, anti-VEGF protein, anti-VEGF aptamer, anti-VEGF antibody,anti-VEGF antibody fragment, anti-VEGF single chain antibody fragment,blocks VEGFR1, blocks VEGFR2, blocks VEGFR3, anti-PDGF, anti-PDGFprotein, anti-PDGF aptamer, anti-PDGF antibody, anti-PDGF antibodyfragment, anti-PDGF single chain antibody fragment, anti-ang2, anti-ang2protein, anti-ang2 aptamer, anti-ang2 antibody, anti-ang2 antibodyfragment, anti-ang2 single chain antibody fragment, anti-angiogenesis,Sunitinib, E7080, Takeda-6d, Tivozanib, Regorafenib, Sorafenib,Pazopanib, Axitinib, Nintedanib, Cediranib, Vatalanib, Motesanib,macrolides, sirolimus, everolimus, tyrosine kinase inhibitors (TKIs),Imatinib (GLEEVAC) gefinitib (IRESSA), toceranib (PALLADIA), Erlotinib(TARCEVA), Lapatinib (TYKERB) Nilotinib, Bosutinib Neratinib, lapatinib,Vatalanib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib,lestaurtinib, nilotinib, semaxanib, toceranib, vandetanib.

The therapeutic agent may comprise a macromolecule, for example anantibody, single chain antibody fragment, or other antibody fragment.The therapeutic macromolecule may comprise a VEGF inhibitor, for exampleranibizumab, the active ingredient in the commercially availableLucentis™. The VEGF (Vascular Endothelial Growth Factor) inhibitor cancause regression of the abnormal blood vessels and improvement of visionwhen released into the vitreous humor of the eye. Examples of VEGFinhibitors include Lucentis™ (ranibizumab), Avastin™ (bevacizumab),Macugen™ (pegaptanib). Platelet derived growth factor (PDGF) inhibitorsmay also be delivered, e.g. Fovista™, an anti-PGDF aptamer.

The therapeutic agent may comprise small molecules such as of a steroidor corticosteroid and analogues thereof. For example, the therapeuticcorticosteroid may comprise one or more of trimacinalone, trimacinaloneacetonide, dexamethasone, dexamethasone acetate, fluocinolone,fluocinolone acetate, loteprednol etabonate, or analogues thereof.Alternatively or in combination, the small molecules of therapeuticagent may comprise a tyrosine kinase inhibitor.

The therapeutic agent may comprise an antiangiogenic or anti-VEGFtherapeutic agent. Anti-VEGF therapies and agents can be used in thetreatment of certain cancers and in age-related macular degeneration.Examples of anti-VEGF therapeutic agents suitable for use in accordancewith the embodiments described herein include one or more of monoclonalantibodies such as bevacizumab (Avastin™) or antibody derivatives suchas ranibizumab (Lucentis™), or small molecules that inhibit the tyrosinekinases stimulated by VEGF such as lapatinib (Tykerb™), sunitinib(Sutent™), sorafenib (Nexavar™), axitinib, or pazopanib.

The therapeutic agent may comprise a therapeutic agent suitable fortreatment of dry AMD such as one or more of Sirolimus™ (Rapamycin),Copaxone™ (Glatiramer Acetate), Othera™ Complement C5aR blocker, CiliaryNeurotrophic Factor, Fenretinide or Rheopheresis.

The therapeutic agent may comprise a therapeutic agent suitable fortreatment of wet AMD such as one or more of REDD14NP (Quark), Sirolimus™(Rapamycin), ATG003; Regeneron™ (VEGF Trap) or complement inhibitor(POT-4).

The therapeutic agent may comprise a kinase inhibitor such as one ormore of bevacizumab (monoclonal antibody), BIBW 2992 (small moleculetargeting EGFR/Erb2), cetuximab (monoclonal antibody), imatinib (smallmolecule), trastuzumab (monoclonal antibody), gefitinib (smallmolecule), ranibizumab (monoclonal antibody), pegaptanib (smallmolecule), sorafenib (small molecule), dasatinib (small molecule),sunitinib (small molecule), erlotinib (small molecule), nilotinib (smallmolecule), lapatinib (small molecule), panitumumab (monoclonalantibody), vandetanib (small molecule) or E7080 (targetingVEGFR2/VEGFR2, small molecule commercially available from Esai, Co.)

Therapeutic agents may include various classes of drugs. Drugs include,for instance, steroids, non-steroidal anti-inflammatory drugs (NSAIDS),anti-cancer drugs, antibiotics, an anti-inflammatory (e.g., Diclofenac),a pain reliever (e.g., Bupivacaine), a Calcium channel blocker (e.g.,Nifedipine), an Antibiotic (e.g., Ciprofloxacin), a Cell cycle inhibitor(e.g., Simvastatin), a protein (e.g., Insulin). Therapeutic agentsinclude classes of drugs including steroids, NSAIDS, antibiotics, painrelievers, inhibitors of vascular endothelial growth factor (VEGF),chemotherapeutics, anti-viral drugs, for instance. Examples of NSAIDSare Ibuprofen, Meclofenamate sodium, mefanamic acid, salsalate,sulindac, tolmetin sodium, ketoprofen, diflunisal, piroxicam, naproxen,etodolac, flurbiprofen, fenoprofen calcium, Indomethacin, celoxib,ketrolac, and nepafenac. The drugs themselves may be small molecules,proteins, RNA fragments, proteins, glycosaminoglycans, carbohydrates,nucleic acid, inorganic and organic biologically active compounds wherespecific biologically active agents include but are not limited to:enzymes, antibiotics, antineoplastic agents, local anesthetics,hormones, angiogenic agents, anti-angiogenic agents, growth factors,antibodies, neurotransmitters, psychoactive drugs, anticancer drugs,chemotherapeutic drugs, drugs affecting reproductive organs, genes, andoligonucleotides, or other configurations.

Therapeutic agents may include a protein or other water solublebiologics. These include peptides and proteins. The term peptide, asused herein, refers to peptides of any size, e.g., at least 1000 Damolecular weight, or from 100-200,000 molecular weight; Artisans willimmediately appreciate that all ranges and values between the explicitlystated bounds are contemplated, with, e.g., any of the following beingavailable as an upper or lower limit: 100, 200, 300, 400, 500, 1000,5,000, 10,000, 20,000, 30,000, 40,000, 50,000, 60,000, 80,000, 100,000,150,000, 200,000. Peptides include therapeutic proteins and peptides,antibodies, antibody fragments, short chain variable fragments (scFv),growth factors, angiogenic factors, and insulin. Other water solublebiologics are carbohydrates, polysaccharides, nucleic acids, antisensenucleic acids, RNA, DNA, small interfering RNA (siRNA), and aptamers.

The therapeutic agents may be used as part of a method of treating theindicated condition or making a composition for treating the indicatedcondition. For example, AZOPT (a brinzolamide opthalmic suspension) maybe used for treatment of elevated intraocular pressure in patients withocular hypertension or open-angle glaucoma. BETADINE in aPovidone-iodine ophthalmic solution may be used for prepping of theperiocular region and irrigation of the ocular surface. BETOPTIC(betaxolol HCl) may be used to lower intraocular pressure, or forchronic open-angle glaucoma and/or ocular hypertension. CILOXAN(Ciprofloxacin HCl opthalmic solution) may be used to treat infectionscaused by susceptible strains of microorganisms. NATACYN (Natamycinopthalmic suspension) may be used for treatment of fungal blepharitis,conjunctivitis, and keratitis. NEVANAC (Nepanfenac opthalmic suspension)may be used for treatment of pain and inflammation associated withcataract surgery. TRAVATAN (Travoprost ophthalmic solution) may be usedfor reduction of elevated intraocular pressure—open-angle glaucoma orocular hypertension. FML FORTE (Fluorometholone ophthalmic suspension)may be used for treatment of corticosteroid-responsive inflammation ofthe palperbral and bulbar conjunctiva, cornea and anterior segment ofthe globe. LUMIGAN (Bimatoprost ophthalmic solution) may be used forreduction of elevated intraocular pressure—open-angle glaucoma or ocularhypertension. PRED FORTE (Prednisolone acetate) may be used fortreatment of steroid-responsive inflammation of the palpebral and bulbarconjunctiva, cornea and anterior segment of the globe. PROPINE(Dipivefrin hydrochloride) may be used for control of intraocularpressure in chronic open-angle glaucoma. RESTASIS (Cyclosporineophthalmic emulsion) may be used to increases tear production inpatients, e.g., those with ocular inflammation associated withkeratoconjunctivitis sicca. ALREX (Loteprednol etabonate ophthalmicsuspension) may be used for temporary relief of seasonal allergicconjunctivitis. LOTEMAX (Loteprednol etabonate ophthalmic suspension)may be used for treatment of steroid-responsive inflammation of thepalpebral and bulbar conjunctiva, cornea and anterior segment of theglobe. MACUGEN (Pegaptanib sodium injection) may be used for Treatmentof neovascular (wet) age-related macular degeneration. OPTIVAR(Azelastine hydrochloride) may be used for treatment of itching of theeye associated with allergic conjunctivitis. XALATAN (Latanoprostophthalmic solution) may be used to reduce elevated intraocular pressurein patients, e.g., with open-angle glaucoma or ocular hypertension.BETIMOL (Timolol opthalmic solution) may be used for treatment ofelevated intraocular pressure in patients with ocular hypertension oropen-angle glaucoma. Latanoprost is the pro-drug of the free acid form,which is a prostanoid selective FP receptor agonist. Latanoprost reducesintraocular pressure in glaucoma patients with few side effects.Latanoprost has a relatively low solubility in aqueous solutions, but isreadily soluble in organic solvents typically employed for fabricationof microspheres using solvent evaporation.

Further embodiments of therapeutic agents for delivery include thosethat specifically bind a target peptide in vivo to prevent theinteraction of the target peptide with its natural receptor or otherligands. AVASTIN, for instance, is an antibody that binds VEGF. Alsoknown are fusion proteins that include at least a portion of a VEGFreceptor to trap VEGF. An IL-1 trap that makes use of the extracellulardomains of IL-1 receptors is also known; the trap blocks IL-1 frombinding and activating receptors on the surface of cells. Embodiments ofagents for delivery include nucleic acids, e.g., aptamers. Pegaptanib(MACUGEN), for example, is a pegylated anti-VEGF aptamer. An advantageof the particle-and-hydrogel delivery process is that the aptamers areprotected from the in vivo environment until they are released. Furtherembodiments of agents for delivery include macromolecular drugs, a termthat refers to drugs that are significantly larger than classical smallmolecule drugs, i.e., drugs such as oligonucleotides (aptamers,antisense, RNAi), ribozymes, gene therapy nucleic acids, recombinantpeptides, and antibodies.

One embodiment comprises extended release of a medication for allergicconjunctivitis. For instance, ketotifen, an antihistamine and mast cellstabilizer, may be provided in particles and released to the eye asdescribed herein in effective amounts to treat allergic conjunctivitis.Seasonal Allergic Conjunctivitis (SAC) and Perennial AllergicConjunctivitis (PAC) are allergic conjunctival disorders. Symptomsinclude itching and pink to reddish eyes. These two eye conditions aremediated by mast cells. Non-specific measures to ameliorate symptomsconventionally include: cold compresses, eyewashes with tearsubstitutes, and avoidance of allergens. Treatment conventionallyconsists of antihistamine mast cell stabilizers, dual mechanismanti-allergen agents, or topical antihistamines. Corticosteroids mightbe effective but, because of side effects, are reserved for more severeforms of allergic conjunctivitis such as vernal keratoconjunctivitis(VKC) and atopic keratoconjunctivitis (AKC).

Oxifloxacin is the active ingredient in VIGAMOX, which is afluoroquinolone approved for use to treat or prevent ophthalmicbacterial infections. Dosage is typically one-drop of a 0.5% solutionthat is administered 3 times a day for a period of one-week or more. VKCand AKC are chronic allergic diseases where eosinophils, conjunctivalfibroblasts, epithelial cells, mast cells, and/or TH2 lymphocytesaggravate the biochemistry and histology of the conjunctiva. VKC and AKCcan be treated by medications used to combat allergic conjunctivitis.Permeation agents are agents and may also be included in a gel,hydrogel, organogel, xerogel, and biomaterials as described herein.These are agents that assist in permeation of a drug into an intendedtissue. Permeation agents may be chosen as needed for the tissue, e.g.,permeation agents for skin, permeation agents for an eardrum, andpermeation agents for an eye.

Controlled Release

TKIs, proteins, and other agents may be controllably released. A firsttechnique is to use a hydrogel to control a rate of release, with theagent being entrapped in the hydrogel until the hydrogel erodes. Asecond technique puts the agent in a particle that controls the rate ofrelease. The particle has to erode to release the agent, or it is madeof a material that limits diffusion of the agent from the particle, orthe particle comprises a release rate agent, with the agent being chosento slow-down release of the agent from the particle. A third techniqueuses a solid agent or concentrated liquid agent that is inside ahydrogel; the hydrogel matrix can be made to limit diffusion of fluid sothat the agent is slow to enter solution because the turn-over of fluidnext to the agent is slow. A fourth technique uses a hydrogel as ratelimiting barrier to control a rate of release; the hydrogel allowsdiffusion of the agent out of the hydrogel without necessarily having tobe eroded for release to take place. These and other techniques may beapplied to controllably release an agent. The size and solubility of theagent, its charge, melting point, hydrophobicity or hydrophilicity, andother physical characteristics can affect the choice of techniques. Thetechniques can be used together, for instance, a hydrogel that limits arate of diffusion in combination with particles that control release.

Embodiments include agents that are particles, or are in particles, thathave a maximum dimension of 0.01 to 100 microns; Artisans willimmediately appreciate that all ranges and values between the explicitlystated bounds are contemplated, with, e.g., any of the following beingavailable as an upper or lower limit: 0.01. 0.02. 0.05. 0.1, 0.5, 0.6,1, 2, 4, 5, 6, 7, 8, 9, 10, 20, 50, 80, 90, 100 microns. The termparticle is broad and encompasses spheres, drops, whiskers, andirregular shapes. Particles include powders or drops of agents that areinsoluble in aqueous solution or that have a low water solubility,meaning a water solubility in the range of about 0.001 to about 0.5mg/ml at 20° C. Agents that are micronized, as per the example withAxitinib herein, are useful in many situations. The particles, in someembodiments, are made with low water soluble lipophilic materials thathave a molecular weight of no more than about 2000. An embodiment of thesystem involves a hydrophilic hydrogel comprising dispersed lipophilicparticles that contain a therapeutic agent. The particles may be madewith molecules that hydrophobic and/or hydrophilic agents may be used.

Certain embodiments of the invention are accomplished by providingcompositions and methods to control the release of relatively lowmolecular weight therapeutic species using hydrogels. A therapeuticagent first is dispersed or dissolved within one or more relativelyhydrophobic rate modifying agents to form a mixture. The mixture may beformed into particles or microparticles, which are then entrapped withina bioabsorbable hydrogel matrix so as to release the water solubletherapeutic agents in a controlled fashion. Alternatively, themicroparticles may be formed in situ during crosslinking of thehydrogel.

In another method, hydrogel microspheres are formed from polymerizablemacromers or monomers by dispersion of a polymerizable phase in a secondimmiscible phase, wherein the polymerizable phase contains at least onecomponent required to initiate polymerization that leads to crosslinkingand the immiscible bulk phase contains another component required toinitiate crosslinking, along with a phase transfer agent. Pre-formedmicroparticles containing the water soluble therapeutic agent may bedispersed in the polymerizable phase, or formed in situ, to form anemulsion. Polymerization and crosslinking of the emulsion and theimmiscible phase is initiated in a controlled fashion after dispersal ofthe polymerizable phase into appropriately sized microspheres, thusentrapping the microparticles in the hydrogel microspheres.Visualization agents may be included, for instance, in the microspheres,microparticles, and/or microdroplets.

Embodiments of the invention include compositions and methods forforming composite hydrogel-based matrices and microspheres havingentrapped therapeutic compounds. In one embodiment, a bioactive agent isentrapped in microparticles having a hydrophobic nature (also termedhydrophobic microdomains), to retard leakage of the entrapped agent. Insome cases, the composite materials that have two phase dispersions,where both phases are absorbable, but are not miscible. For example, thecontinuous phase may be a hydrophilic network (such as a hydrogel, whichmay or may not be crosslinked) while the dispersed phase may behydrophobic (such as an oil, fat, fatty acid, wax, fluorocarbon, orother synthetic or natural water immiscible phase, generically referredto herein as an “oil” or “hydrophobic” phase). The oil phase entraps thedrug and provides a barrier to release by slow partitioning of the druginto the hydrogel. The hydrogel phase in turn protects the oil fromdigestion by enzymes, such as lipases, and from dissolution by naturallyoccurring lipids and surfactants. The latter are expected to have onlylimited penetration into the hydrogel, for example, due tohydrophobicity, molecular weight, conformation, diffusion resistance,etc. In the case of a hydrophobic drug which has limited solubility inthe hydrogel matrix, the particulate form of the drug may also serve asthe release rate modifying agent. Visualization agents may be included,for instance, in the gel matrix or the microdomains.

In one embodiment, a microemulsion of a hydrophobic phase and an aqueoussolution of a water soluble molecular compound, such as a protein,peptide or other water soluble chemical is prepared. The emulsion is ofthe “water-in-oil” type (with oil as the continuous phase) as opposed toan “oil-in-water” system (where water is the continuous phase). Otheraspects of drug delivery are found in U.S. Pat. Nos. 6,632,457;6,379,373; and 6,514,534, each of which are hereby incorporated byreference.

Controlled rates of drug delivery also may be obtained by degradable,covalent attachment of the agents to the crosslinked hydrogel network.The nature of the covalent attachment can be controlled to enablecontrol of the release rate from hours to weeks or years. By using acomposite made from linkages with a range of hydrolysis times, acontrolled release profile may be extended for longer durations.Polymers that include ester linkages may also be included to provide adesired degradation rate of a hydrogel, of a particle, or an attachmentlinkage, with groups being added or subtracted near the esters toincrease or decrease the rate of degradation. Thus it is possible toconstruct a hydrogel with a desired degradation profile, from a few daysto many months, using a degradable segment. If polyglycolate is used asthe biodegradable segment, for instance, a crosslinked polymer could bemade to degrade in about 1 to about 30 days depending on thecrosslinking density of the network. Similarly, a polycaprolactone basedcrosslinked network can be made to degrade in about 1 to about 8 months.The degradation time generally varies according to the type ofdegradable segment used, in the following order:polyglycolate<polylactate<polytrimethylene carbonate<polycaprolactone.Thus it is possible to construct a hydrogel with a desired degradationprofile, from a few days to many months, using a degradable segment.

Embodiments of the invention include a prosthesis that controllablyreleases an amount of an agent over a period of time from 1 day to 5years; Artisans will immediately appreciate that all ranges and valuesbetween the explicitly stated bounds are contemplated, with, e.g., anyof the following being available as an upper or lower limit: 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23,24 months, 1, 1.5, 2, 2.5, 3, 3.5, 4. 4.5, 5 years. The amount of theagent released in the period of time may vary from, e.g., 10% to 100%w/w; Artisans will immediately appreciate that all ranges and valuesbetween the explicitly stated bounds are contemplated, with, e.g., anyof the following being available as an upper or lower limit: 10, 20, 30,40, 50, 60, 70 80, 90, 95, 99, 100 percent w/w of the agent is released.For example, applying these values, a plot of a cumulative release of anagent versus tine may be used to show a release of 50% or 80% w/w of anagent is reached at a time that falls within 1-24 months: e.g., 1, 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,23, 24 months. During the time of release, the released concentrationmay be provided to a tissue, e.g., an eye or a retina, in an effectiveamount, meaning at least the IC50 of effectiveness (inhibition for aninhibiting agent, activating for an activating agent).

Kits or Systems

Kits may be made that comprise one or more components set forth herein.For instance, the kit may have an applicator and a shape-changingvehicle. The kits are manufactured using medically acceptable conditionsand contain components that have sterility, purity and preparation thatis pharmaceutically acceptable. Solvents/solutions or diluents may beprovided in the kit or separately. The kit may include syringes and/orneedles for mixing and/or delivery. Instructions for carrying out one ormethods set forth herein may be provided.

EXAMPLES

Some precursors are referred to by a nomenclature of naxxKpppfff, wheren is the number of arms, xx is the molecular weight (MW), ppp is thepolymer, and fff is the functional end group. Thus 8a15KPEGSAP refers toan 8-armed Polyethylene glycol (PEG) with a MW of 15,000 g/mol=15K PEG.Succinimidyl adipate is: SAP. Succinimidyl glutarate is SG.

Examples Coiling Bi-Polymeric Fibers Example 1 Coiling HydrogelBi-Polymeric Fiber Fiber Formation

Buffer 1: Sodium phosphate dibasic (240 mg) was dissolved in deionized(DI) water and made up to 10 mL (24 mg/mL).

Buffer 2: Sodium phosphate monobasic (462.4 mg) was dissolved indeionized (DI) water and made up to 50 mL (9.25 mg/mL).

Syringe 1: Polyethylene glycol (PEG), MW=20 kDa, 4 arms (initiated withpentaerythritol), each arm end-capped with succimimidyl glutarate (4a20kPEG SG, 16.7 mg) was weighed into a 1 mL, polyethylene (PE) syringe (BD)and dissolved in 108.4 mg of Buffer 2.

Syringe 2: Polyethylene glycol (PEG), MW=20 kDa, 8 arms (initiated withhexaglycerol), each arm end-capped with amine (8a20k PEG NH₂, 8.3 mg)was weighed into a 1 mL, PE syringe (BD) and dissolved in 116.7 mg ofBuffer 1.

The contents of syringe 1 and syringe 2 were mixed and injected intofour segments of silicone tubing, each approximately 25 cm long, havingan inner diameter of approximately 0.51 mm (Dow Corning Silastic,catalogue #508-002) using a 21 G needle (BD). After gelation wasconfirmed, each tube was then transferred into a 37° C. chamber (BinderOven, model # ED-115 UL) under a nitrogen sweep to dry for about 9 days.

Each dried strand was gently stretched by manually pulling gently onboth ends, causing necking, to form an oriented fiber along its fulllength. The final draw ratio was about 4 times the original length. Thenecked fiber was pulled into a length of polyethylene tubing having aninner diameter of approximately 0.58 mm (Intramedic, catalogue # 427411)and the tubing was cut to a length approximately 3 cm shorter than thefiber. A 1.5 cm segment remained exposed outside of each end of thetubing, and each end of the taut fiber was taped to the side of a 1liter glass beaker using laboratory tape. The curvature of the beakerwas used to maintain the fiber tight against the inside wall of thetube.

Second Layer

Syringe 3: 2.5 mg of 8a20k PEG NH₂ was weighed into a 1 mL PE syringeand dissolved in 122.5 mg of the buffer 1 and a trace amount ofLissamine Green B for visualization.

Syringe 4: Polyethylene glycol (PEG), MW=40 kDa, 4 arms (initiated withpentaerythritol), each arm end-capped with succimimidyl adipate (4a20kPEG SAP, 10 mg) was weighed into a 1 mL PE syringe and dissolved in 115mg of Buffer 2.

The contents of the syringes 3 and 4 were mixed and then injectedthrough a 25 G BD needle into one end of the polyethylene tubingcontaining the fiber, filling the lumen to coat the fiber while thefiber was held in tension, and the coating was allowed to gel. Aftergelation of the coating, the sample, still attached to the beaker, wastransferred into the 37° C. chamber (Binder Oven, model # ED-115 UL)under a nitrogen sweep, where it remained for approximately 3.5 days.The tubing was cut to approximately 1 cm segments and the fibercarefully removed from each segment. The diameter of coated fibermeasured between 0.12 mm to 0.14 mm.

Hydration and Coiling in PBS and HA/PBS Solutions

A small amount of phosphate buffered saline (PBS) solution was heated toapproximately 37° C. in a plastic weigh boat on a hot plate. A coatedfiber segment was then placed in a second weigh boat. Using a 3 mLtransfer pipette, a few droplets of the PBS were added to the fiber. Thefiber rapidly retracted into a uniform helical coil in less than 15seconds. This hydration was video recorded and digitally photographed,see FIGS. 10A-10C.

A small plastic weigh boat was placed on a hot plate, and severaldroplets of 2.0% sodium hyaluronate (MW=850 KDa) (HA) solution in PBSwere added to the weigh boat. The viscosity of the HA/PBS solution wasintended to simulate rabbit vitreous humor. The solution was heated toapproximately 37° C. A coated fiber segment was placed into this viscoussolution at 37° C., and again coiled in less than 15 seconds into auniform helical shape, indicating the increase in viscosity did notsignificantly retard the coil formation. This hydration was videorecorded and digitally photographed, see FIGS. 11A-11C.

Example 2 Fluorescein Conjugated Hydrogel Bi-Polymeric Coil Examples

Two additional hydrogel formulations were used to create coilingbi-polymeric fibers.

Buffer 1: Sodium phosphate monobasic (904.4 mg) was dissolved indeionized (DI) water and made up to 100 mL (9 mg/mL).

Buffer 2: Sodium phosphate dibasic (2.4301 g) was dissolved in deionized(DI) water and made up to 100 mL (24.3 mg/mL).

Amine Solution: Polyethylene glycol (PEG), MW=20 kDa, 8 arms (initiatedwith hexaglycerol), each arm end-capped with amine (8a20k PEG NH₂, 715.9mg) and NHS-Fluorescein (15.0 mg) were dissolved in Buffer 2 and made upto 10 mL. Resulting solution was held overnight, with the vessel wrappedin foil to minimize light exposure.

Example 2A Fiber Formation

Syringe 1A: Polyethylene glycol (PEG), MW=20 kDa, 4 arms (initiated withpentaerythritol), each arm end-capped with succinimidyl glutarate (4a20kPEG SG, 166.2 mg) was dissolved in 1.157 mL of Buffer 1. Transferredresulting solution (125 μL) into a 1 mL polyethylene (PE) syringe (BD).

Syringe 2A: Amine solution was transferred (125 μL) into a 1 mL PEsyringe (BD).

The contents of Syringe 1A and Syringe 2A were mixed and injected intofour segments of Dow Corning Silastic silicone tubing (cat. # 508-002),each approximately 25 cm long, having an inner diameter of approximately0.51 mm using a 21 G needle. After gelation was confirmed, each tube wasthen transferred into a 37° C. chamber (Binder Oven, model # ED-115 UL)under a nitrogen sweep to dry for about 3 days.

The dried strand was gently stretched by manually pulling gently on bothends, causing necking, to form an oriented fiber along its full length.The final draw ratio was about 4 times the original length. The neckedfiber was pulled into a length of polyethylene tubing (cat. # 427411)having an inner diameter of approximately 0.58 mm and the tubing was cutto a length approximately 3 cm shorter than the fiber. A 1.5 cm segmentremained exposed outside of each end of the tubing, and each end of thetaut fiber was taped to the side of an aluminum weigh boat usinglaboratory tape. The curvature of the weigh boat was used to maintainthe fiber tight against the inside wall of the tube.

Second Layer

Syringe 3A: Polyethylene glycol (PEG), MW=40 kDa, 4 arms (initiated withpentaerythritol), each arm end-capped with succinimidyl adipate (4a40kPEG SAP, 101.3 mg) was dissolved in 1.15 mL of Buffer 1. Resultingsolution was transferred (125 μL) into a 1 mL polyethylene (PE) syringe(BD).

Syringe 4A: The Amine Solution (5 mL) was diluted using Buffer 2 andmade up to 10 mL. Resulting solution was transferred (125 μL) into a 1mL PE syringe (BD).

The contents of the syringes 3A and 4A were mixed and injected into oneend of the polyethylene tubing containing the fiber, filling the lumento coat the fiber while the fiber was held in tension, and the coatingwas allowed to gel. After gelation of the coating, the sample, stillattached to the weigh boat, was transferred into the 37° C. chamberunder a nitrogen sweep, where it remained for approximately 7 days.

After drying, the coated strand was cut away from the weigh boat. Thepolyethylene tubing was cut into segments approximately 12 mm in length,and the resulting segments of coated fibers were removed from thetubing. The coated fiber segments were placed in a vial and capped forstorage.

Example 2B

Syringe 1B: Polyethylene glycol (PEG), MW=20 kDa, 4 arms (initiated withpentaerythritol), each arm end-capped with succinimidyl adipate (4a20kPEG SAP, 1.774 mg) was dissolved in 1.157 mL of Buffer 1. Transferredresulting solution (125 μL) into a 1 mL polyethylene (PE) syringe (BD).

Syringe 2B: Amine solution was transferred (125 μL) into a 1 mL PEsyringe (BD).

The contents of Syringe 1B and Syringe 2B were mixed and injected intofour segments of silicone tubing, each approximately 25 cm long, havingan inner diameter of approximately 0.51 mm using a 21 G needle. Aftergelation was confirmed, each tube was then transferred into a 37° C.chamber under a nitrogen sweep to dry for about 3 days.

The dried strand was gently stretched by manually pulling gently on bothends, causing necking, to form an oriented fiber along its full length.The final draw ratio was about 4 times the original length. The neckedfiber was pulled into a length of polyethylene tubing having an innerdiameter of approximately 0.58 mm and the tubing was cut to a lengthapproximately 3 cm shorter than the fiber. A 1.5 cm segment remainedexposed outside of each end of the tubing, and each end of the tautfiber was taped to the side of an aluminum weigh boat using laboratorytape. The curvature of the weigh boat was used to maintain the fibertight against the inside wall of the tube.

Syringe 3B: Weighed 4a40k PEG SAP (20.1 mg) into a 1 mL PE syringe (BD)and dissolved in 105 μL of Buffer 1.

Syringe 4B: Amine solution was transferred (125 μL) into a 1 mL PEsyringe (BD).

The contents of the syringes 3B and 4B were mixed and injected into oneend of the polyethylene tubing containing the fiber, filling the lumento coat the fiber while the fiber was held in tension, and the coatingwas allowed to gel. After gelation of the coating, the sample, stillattached to the weigh boat, was transferred into the 37° C. chamberunder a nitrogen sweep, where it remained for approximately 7 days.

After drying, the coated strand was cut away from the weigh boat. Thepolyethylene tubing was cut into segments approximately 12 mm in length,and the resulting segments of coated fibers were removed from thetubing. The coated fiber segments were placed in a vial and capped forstorage.

Example 3 Fluorescein Conjugated Organogel Bi-Polymeric Coil ExamplesExample 3A Fiber Formation

Syringe 1A: Polyethylene glycol (PEG), MW=20 kDa, 4 arms (initiated withpentaerythritol), each arm end-capped with succinimidyl glutarate (4a20kPEG SG, 202.4 mg) was dissolved in 1.39 mL Dimethyl Carbonate (DMC) in a10 mL vial. Vial was immediately stoppered to seal. Resulting solutionwas transferred (125 μL) into a 1 mL polyethylene (PE) syringe (BD).

Syringe 2A: Polyethylene glycol (PEG), MW=20 kDa, 8 arms (initiated withhexaglycerol), each arm end-capped with amine (8a20k PEG NH₂, 159.7 mg)and NHS-Fluorescein (3.4 mg) were dissolved in DMC (2.08 mL) in a 10 mLvial. Vial was immediately stoppered to seal. Resulting solution washeld overnight, then transferred (125 μL) into a 1 mL PE syringe (BD).

The contents of Syringe 1A and Syringe 2A were mixed and injected intofour segments of silicone tubing, each approximately 25 cm long, havingan inner diameter of approximately 0.51 mm using a 21 G needle. Aftergelation was confirmed, each tube was then transferred into a 37° C.chamber under a nitrogen sweep to dry overnight.

Each dried strand was gently stretched by manually pulling gently onboth ends, causing necking, to form an oriented fiber along its fulllength. The final draw ratio was about 4 times the original length. Thenecked fiber was pulled into a length of polyethylene tubing having aninner diameter of approximately 0.58 mm and the tubing was cut to alength approximately 3 cm shorter than the fiber. A 1.5 cm segmentremained exposed outside of each end of the tubing, and each end of thetaut fiber was taped to the side of an aluminum weigh boat usinglaboratory tape. The curvature of the weigh boat was used to maintainthe fiber tight against the inside wall of the tube.

Second Layer

Syringe 3A: Weighed Polyethylene glycol (PEG), MW=40 kDa, 4 arms(initiated with pentaerythritol), each arm end-capped with succinimidyladipate (4a40k PEG SAP, 201.8 mg) and dissolved in 2.3 mL of DMC in a 10mL vial. Vial was immediately stoppered to seal. Resulting solution wastransferred (125 μL) into a 1 mL PE syringe (BD).

Syringe 4A: Transferred same solution as used for Syringe2 (62.5 μL)into a 1 mL PE syringe (BD). Added DMC (62.5 μL) to the syringe todilute.

The contents of the syringes 3A and 4A were mixed and injected into oneend of the polyethylene tubing containing the fiber, filling the lumento coat the fiber while the fiber was held in tension, and the coatingwas allowed to gel. After gelation of the coating, the sample, stillattached to the weigh boat, was transferred into the 37° C. chamberunder a nitrogen sweep, where it remained overnight.

After drying, the coated strand was cut away from the weigh boat. Thepolyethylene tubing was cut into segments approximately 12 mm in length,and the resulting segments of coated fibers were removed from thetubing. The coated fiber segments were placed in a 10 mL vial and cappedfor storage. The diameter of the segments was measured to be between0.16 mm-0.18 mm. An image of the dried fiber is presented in FIG. 13A.

Example 3B Fiber Formation

Syringe 1B: Polyethylene glycol (PEG), MW=20 kDa, 4 arms (initiated withpentaerythritol), each arm end-capped with succinimidyl adipate (4a20kPEG SAP, 203.4 mg) was dissolved in 1.4 mL Dimethyl Carbonate (DMC) in a10 mL vial. Vial was immediately stoppered to seal. Resulting solutionwas transferred (125 μL) into a 1 mL polyethylene (PE) syringe (BD).

Syringe 2 B: Polyethylene glycol (PEG), MW=20 kDa, 8 arms (initiatedwith hexaglycerol), each arm end-capped with amine (8a20k PEG NH₂, 200mg) and NHS-Fluorescein (4.1 mg) were dissolved in DMC (2.6 mL) in a 10mL vial. Vial was immediately stoppered to seal. Resulting solution washeld overnight, then transferred (125 μL) into a 1 mL PE syringe (BD).

The contents of Syringe 1B and Syringe 2B were mixed and injected intofour segments of silicone tubing, each approximately 25 cm long, havingan inner diameter of approximately 0.51 mm using a 21 G needle. Aftergelation was confirmed, each tube was then transferred into a 37° C.chamber under a nitrogen sweep to dry overnight.

Each dried strand was gently stretched by manually pulling gently onboth ends, causing necking, to form an oriented fiber along its fulllength. The final draw ratio was about 4 times the original length. Thenecked fiber was pulled into a length of polyethylene tubing having aninner diameter of approximately 0.58 mm and the tubing was cut to alength approximately 3 cm shorter than the fiber. A 1.5 cm segmentremained exposed outside of each end of the tubing, and each end of thetaut fiber was taped to the side of an aluminum weigh boat usinglaboratory tape. The curvature of the weigh boat was used to maintainthe fiber tight against the inside wall of the tube.

Second Layer

Syringe 3B: Transferred same solution used in Syringe 1B (125 μL) into a1 mL PE syringe (BD).

Syringe 4B: Transferred same solution used in Syringe 2B (125 μL) into a1 mL PE syringe (BD).

The contents of the syringes 3B and 4B were mixed and injected into oneend of the polyethylene tubing containing the fiber, filling the lumento coat the fiber while the fiber was held in tension, and the coatingwas allowed to gel. After gelation of the coating, the sample, stillattached to the weigh boat, was transferred into the 37° C. chamberunder a nitrogen sweep, where it remained overnight.

After drying, the coated strand was cut away from the weigh boat. Thepolyethylene tubing was cut into segments approximately 12 mm in length,and the resulting segments of coated fibers were removed from thetubing. The coated fiber segments were placed in a 10 mL vial and cappedfor storage. The diameter of the segments was measured to be between0.21 mm-0.24 mm. An image of the dried fiber is presented in FIG. 13B.

Hydration and Coiling

A small plastic weigh boat was placed on a hot plate, and severaldroplets of 2.0% sodium hyaluronate (MW=850 KDa) (HA) solution in PBSwere added to the weigh boat. The viscosity of the HA/PBS solution wasintended to simulate rabbit vitreous humor. The solution was heated toapproximately 37° C. A coated fiber segment from Example 3A was placedinto this viscous solution at 37° C., and coiled in less than 15 secondsinto a helical shape.

Similarly, several droplets of 2.0% HA solution in PBS were added to asecond weigh boat and heated to approximately 37° C. and a coated fibersegment from Example 3B was placed into the solution. This sample alsocoiled in less than 15 seconds. FIGS. 13C and 13D are photographs of thefiber taken from different perspectives.

Example 4 Coiling Hydrogel Fibers Containing Axitinib Fiber Formation

Buffer 1: Sodium phosphate dibasic (240 mg) was dissolved in deionized(DI) water and made up to 10 mL (24 mg/mL).

Buffer 2: Sodium phosphate monobasic (462.4 mg) was dissolved indeionized (DI) water and made up to 50 mL (9.25 mg/mL).

Syringe 1: Polyethylene glycol (PEG), MW=20 KDa, 4 arms (initiated withpentaerythritol), each arm end-capped with succimimidyl adipate (4a20kPEG SAP, 16.7 mg) was weighed into a 1 mL, polyethylene (PE) syringe(BD) and dissolved in 108.4 mg of Buffer 2.

Syringe 2: Polyethylene glycol (PEG), MW=20 KDa, 8 arms (initiated withhexaglycerol), each arm end-capped with amine (8a20k PEG NH₂, 8.3 mg)was weighed into a 1 mL, PE syringe (BD) and dissolved in 116.7 mg ofBuffer 1.

The contents of syringe 1 and syringe 2 were mixed and injected intofour segments of silicone tubing, each approximately 25 cm long, havingan inner diameter of approximately 0.51 mm using a 21 G needle. Aftergelation was confirmed, each tube was then transferred into a 37° C.chamber under a nitrogen sweep to dry for about 9 days. Each driedstrand was gently stretched by manually pulling gently on both ends,causing necking, to form an oriented fiber along its full length. Thefinal draw ratio was 4.5.

The necked fiber was pulled into a length of polyethylene tubing havingan inner diameter of approximately 0.58 mm and the tubing was cut to alength approximately 3 cm shorter than the fiber. A 1.5 cm segmentremained exposed outside of each end of the tubing, and each end of thetaut fiber was taped to the side of a 140 mm aluminum weigh boat usinglaboratory tape. The curvature of the weigh boat was used to maintainthe fiber's tautness against the inside wall of the tube.

Second Layer with Drug

Syringe 3: 9.0 mg of 8a20k PEG NH₂ was weighed into a 1 mL PE syringeand dissolved in 126 mg of the buffer 1.

Syringe 4: 18.0 mg of Polyethylene glycol (PEG), MW=20 KDa, 4 arms(initiated with pentaerythritol), each arm end-capped with succimimidyladipate (4a20k PEG SAP) was weighed into a 1 mL PE syringe and dissolvedin 117 mg of Buffer 2.

Syringe 5: 30 mg of micronized Axitinib was weighed into a cappedsyringe.

The contents of the syringes 3 and 5 were mixed vigorously using a luerto luer connector. The contents of these syringes were thenquantitatively transferred into one syringe, capped, and sonicated for 5minutes to disperse all agglomerates. The contents of this syringe werethen mixed with syringe 4 and injected into one end of the polyethylenetubing containing the fiber, filling the lumen to coat the fiber whilethe fiber was held in tension, and the coating was allowed to gel.

After gelation of the coating, the sample, still attached to the weightboat, was transferred into the 37° C. chamber under a nitrogen sweep,where it remained for approximately 3.5 days. The tubing was cut toapproximately 1 cm segments and the fiber carefully removed from eachsegment. The diameter of coated fiber measured between 0.12 mm to 0.14mm.

Example 5 Coiling Organogel Fibers Containing Bovine IgG Fiber Formation

Buffer 1: Sodium phosphate dibasic (240 mg) was dissolved in deionized(DI) water and made up to 10 mL (24 mg/mL).

Buffer 2: Sodium phosphate monobasic (462.4 mg) was dissolved indeionized (DI) water and made up to 50 mL (9.25 mg/mL).

Syringe 1: Polyethylene glycol (PEG), MW=20 KDa, 4 arms (initiated withpentaerythritol), each arm end-capped with succimimidyl adipate (4a20kPEG SAP, 16.7 mg) was weighed into a 1 mL, polyethylene (PE) syringe(BD) and dissolved in 108.4 mg of Buffer 2.

Syringe 2: Polyethylene glycol (PEG), MW=20 KDa, 8 arms (initiated withhexaglycerol), each arm end-capped with amine (8a20k PEG NH₂, 8.3 mg)was weighed into a 1 mL, PE syringe (BD) and dissolved in 116.7 mg ofBuffer 1.

The contents of syringe 1 and syringe 2 were mixed and injected intofour segments of silicone tubing, each approximately 25 cm long, havingan inner diameter of approximately 0.51 mm using a 21 G needle. Aftergelation was confirmed, each tube was then transferred into a 37° C.chamber under a nitrogen sweep to dry for about 9 days. Each driedstrand was gently stretched by manually pulling gently on both ends,causing necking, to form an oriented fiber along its full length. Thefinal draw ratio was 4.5.

The necked fiber was pulled into a length of polyethylene tubing havingan inner diameter of approximately 0.58 mm and the tubing was cut to alength approximately 3 cm shorter than the fiber. A 1.5 cm segmentremained exposed outside of each end of the tubing, and each end of thetaut fiber was taped to the side of a 140 mm aluminum weigh boat usinglaboratory tape. The curvature of the weigh boat was used to maintainthe fiber's tautness against the inside wall of the tube.

Second Layer with Drug

Syringe 3: 9.0 mg of 8a20k PEG NH₂ was weighed into a 1 mL PE syringeand dissolved in 126 mg of the Dimethyl carbonate.

Syringe 4: 18.0 mg of Polyethylene glycol (PEG), MW=20 KDa, 4 arms(initiated with pentaerythritol), each arm end-capped with succimimidyladipate (4a20k PEG SAP) was weighed into a 1 mL PE syringe and dissolvedin 117 mg of Dimethyl carbonate.

Syringe 5: 30 mg of micronized Axitinib (see Micronization of Axitinibby Precipitation) was weighed into a capped syringe.

The contents of the syringes 3 and 5 were mixed vigorously using a luerto luer connector. The contents of these syringes were thenquantitatively transferred into one syringe, capped, and sonicated for 5minutes to disperse all agglomerates. The contents of this syringe werethen mixed with syringe 4 and injected into one end of the polyethylenetubing containing the fiber, filling the lumen to coat the fiber whilethe fiber was held in tension, and the coating was allowed to gel. Aftergelation of the coating, the sample, still attached to the weight boat,was transferred into the 37° C. chamber under a nitrogen sweep, where itremained for overnight. The tubing was cut to approximately 1 cmsegments and the fiber carefully removed from each segment. The diameterof coated fiber measured between 0.12 mm to 0.14 mm.

Example 6 Dimensions and Persistence of Coiling Bi-Polymeric FibersContaining Bovine IgG

Samples each consisted of coiling fiber comprised of a necked strand ofPolyethylene glycol (PEG), MW=15 kDa, 8 arms (initiated withpentaerythritol), each arm end-capped with succinimidyl adipate (8a15kPEG SAP, 4%), Polyethylene glycol (PEG), MW=20 kDa, 8 arms (initiatedwith hexaglycerol), each arm end-capped with amine (8a20k PEG NH₂,5.9%), and NHS-Fluorescein (0.1%), and a coating of 8a15k PEG SAP (4%),8a20k PEG NH₂(5.9%), NHS-Fluorescein (0.1%), and Bovine IgG (10%).Details provided above are not repeated.

Fibers were cut to approximately 10 mm lengths. Fiber diameters weremeasured to be between 0.25 mm-0.30 mm. Several droplets of PhosphateBuffered Saline (PBS) solution (pH 7.4) were deposited into four smallweigh boats and heated to approximately 37° C. on a hot plate. Eachfiber sample was hydrated in a weigh boat of PBS solution forapproximately 30 minutes. Samples rapidly coiled into helical coils uponhydration. After 30 minutes, each sample was measured to characterizethe hydrated coil dimensions. FIGS. 14A-14B depicts the dimensionsmeasures, and measured values are provided in the following table:

Dimensions Measured For Each Hydrated Coil At t = 30 Minutes. (Note thatW and D are the same). L Ø d D 1.8 mm- 0.57 mm- 0.34 mm- 1.5 mm- 2.1 mm0.70 mm 0.65 mm 2.2 mm

Following dimensional measurements, each coil was placed into a 10 mLvial filled with Tris Buffered Saline (TBS) solution (pH 8.51) andtransferred into a 37° C. chamber. Coils were observed periodically overthe course of storage at 37° C. and remained in a coiled shape forbetween 7 to 8 days, at which time the coils began to unravel. Theremnants of these coils began to break apart between 8 and 9 days ofstorage in TBS pH 8.51 at 37° C.

Example 7 Coiling Hydrogel Fiber Containing Fast Degrading Necked Fiber

Using a rapidly degrading necked fiber results in increased exposedsurface area once the necked portion has dissolved. Changing thegeometry of the necked portion, particularly diameter, will directlyaffect the amount of increased surface area exposed once the neckedfiber degrades.

Fiber Formation

Buffer 1: Sodium phosphate dibasic (240 mg) was dissolved in deionized(DI) water and made up to 10 mL (24 mg/mL).

Buffer 2: Sodium phosphate monobasic (462.4 mg) was dissolved indeionized (DI) water and made up to 50 mL (9.25 mg/mL).

Syringe 1: Polyethylene glycol (PEG), MW=20 KDa, 4 arms (initiated withpentaerythritol), each arm end-capped with succimimidyl succinate (8a15kPEG SS, 5.4 mg) was weighed into a 1 mL, polyethylene (PE) syringe (BD)and dissolved in 119.6 mg of Buffer 2.

Syringe 2: Polyethylene glycol (PEG), MW=20 KDa, 8 arms (initiated withhexaglycerol), each arm end-capped with amine (8a20k PEG NH₂, 7.1 mg)was weighed into a 1 mL, PE syringe (BD) and dissolved in 117.9 mg ofBuffer 1.

The contents of syringe 1 and syringe 2 were mixed and injected intofour segments of silicone tubing, each approximately 25 cm long, havingan inner diameter of approximately 0.51 mm using a 21 G needle. Aftergelation was confirmed, each tube was then transferred into a 37° C.chamber under a nitrogen sweep to dry for about 9 days. Each driedstrand was gently stretched by manually pulling gently on both ends,causing necking, to form an oriented fiber along its full length. Thefinal draw ratio was 4.5.

The necked fiber was pulled into a length of polyethylene tubing havingan inner diameter of approximately 0.58 mm and the tubing was cut to alength approximately 3 cm shorter than the fiber. A 1.5 cm segmentremained exposed outside of each end of the tubing, and each end of thetaut fiber was taped to the side of a 140 mm aluminum weigh boat usinglaboratory tape. The curvature of the weigh boat was used to maintainthe fiber's tautness against the inside wall of the tube.

Second Layer with Drug

Syringe 3: 9.0 mg of 8a20k PEG NH₂ was weighed into a 1 mL PE syringeand dissolved in 126 mg of the buffer 1.

Syringe 4: 18.0 mg of Polyethylene glycol (PEG), MW=20 KDa, 4 arms(initiated with pentaerythritol), each arm end-capped with succimimidyladipate (4a20k PEG SAP) was weighed into a 1 mL PE syringe and dissolvedin 117 mg of buffer 2.

Syringe 5: 30 mg of micronized Axitinib (see Micronization of Axitinibby Precipitation) was weighed into a capped syringe.

The contents of the syringes 3 and 5 were mixed vigorously using a luerto luer connector. The contents of these syringes were thenquantitatively transferred into one syringe, capped, and sonicated for 5minutes to disperse all agglomerates. The contents of this syringe werethen mixed with syringe 4 and injected into one end of the polyethylenetubing containing the fiber, filling the lumen to coat the fiber whilethe fiber was held in tension, and the coating was allowed to gel. Aftergelation of the coating, the sample, still attached to the weight boat,was transferred into the 37° C. chamber under a nitrogen sweep, where itremained for overnight. The tubing was cut to approximately 1 cmsegments and the fiber carefully removed from each segment. The diameterof coated fiber measured between 0.12 mm to 0.14 mm.

Example 8 Coiling Organogel Fiber Containing Fast Degrading Necked FiberFiber Formation

Buffer 1: Sodium phosphate dibasic (240 mg) was dissolved in deionized(DI) water and made up to 10 mL (24 mg/mL).

Buffer 2: Sodium phosphate monobasic (462.4 mg) was dissolved indeionized (DI) water and made up to 50 mL (9.25 mg/mL).

Syringe 1: Polyethylene glycol (PEG), MW=20 KDa, 4 arms (initiated withpentaerythritol), each arm end-capped with succimimidyl succinate (8a15kPEG SS, 5.4 mg) was weighed into a 1 mL, polyethylene (PE) syringe (BD)and dissolved in 119.6 mg of Buffer 2.

Syringe 2: Polyethylene glycol (PEG), MW=20 KDa, 8 arms (initiated withhexaglycerol), each arm end-capped with amine (8a20k PEG NH₂, 7.1 mg)was weighed into a 1 mL, PE syringe (BD) and dissolved in 117.9 mg ofBuffer 1.

The contents of syringe 1 and syringe 2 were mixed and injected intofour segments of silicone tubing, each approximately 25 cm long, havingan inner diameter of approximately 0.51 mm using a 21 G needle. Aftergelation was confirmed, each tube was then transferred into a 37° C.chamber under a nitrogen sweep to dry for about 9 days. Each driedstrand was gently stretched by manually pulling gently on both ends,causing necking, to form an oriented fiber along its full length. Thefinal draw ratio was 4.5.

The necked fiber was pulled into a length of polyethylene tubing havingan inner diameter of approximately 0.58 mm and the tubing was cut to alength approximately 3 cm shorter than the fiber. A 1.5 cm segmentremained exposed outside of each end of the tubing, and each end of thetaut fiber was taped to the side of a 140 mm aluminum weigh boat usinglaboratory tape. The curvature of the weigh boat was used to maintainthe fiber's tautness against the inside wall of the tube.

Second Layer with Drug

Syringe 3: 9.0 mg of 8a20k PEG NH₂ was weighed into a 1 mL PE syringeand dissolved in 126 mg of the Dimethyl carbonate.

Syringe 4: 18.0 mg of Polyethylene glycol (PEG), MW=20 KDa, 4 arms(initiated with pentaerythritol), each arm end-capped with succimimidyladipate (4a20k PEG SAP) was weighed into a 1 mL PE syringe and dissolvedin 117 mg of Dimethyl carbonate.

Syringe 5: 30 mg of micronized Axitinib (by precipitation) was weighedinto a capped syringe.

The contents of the syringes 3 and 5 were mixed vigorously using a luerto luer connector. The contents of these syringes were thenquantitatively transferred into one syringe, capped, and sonicated for 5minutes to disperse all agglomerates. The contents of this syringe werethen mixed with syringe 4 and injected into one end of the polyethylenetubing containing the fiber, filling the lumen to coat the fiber whilethe fiber was held in tension, and the coating was allowed to gel. Aftergelation of the coating, the sample, still attached to the weight boat,was transferred into the 37° C. chamber under a nitrogen sweep, where itremained for overnight. The tubing was cut to approximately 1 cmsegments and the fiber carefully removed from each segment. The diameterof coated fiber measured between 0.12 mm to 0.14 mm.

Example 9 Micronization of Axitinib by Precipitation AxitinibMicronization

195 mg of Axitinib (manufactured by LGM Pharma, GMP grade) was dissolvedinto 110 mL of Ethanol (Sigma Aldrich) in a glass serum vial, capped andcrimped (1.77 mg Axitinib/mL ethanol). This vial was then wrapped inaluminum foil to protect the solution from light, and sonicated for 20minutes until completely dissolved. Solution was then aspirated into two60 mL polyethylene (PE) luer-lok syringes (BD) wrapped in aluminum foil.

Axitinib Precipitation

1800 mL of sterile Water For Injection (WFI) was measured into a 2 Lbeaker and placed on a stir plate stirring at 600 RPM with a stir bar,creating a large WFI vortex in the center of the beaker. One 60 mL BDsyringe containing axitinib in ethanol was placed on a syringe pumpwhich had been clamped above the WFI beaker. A hypodermic needle (21 G,BD) was connected to the syringe and aimed directly into the center ofthe vortex for dispensation of the axitinib solution. The syringe pumpwas then run at 7.5 mL/min in order to add the axitinib solutiondropwise to the WFI to precipitate micronized Axitinib.

Axitinib Suspension Filtration and Collection

After micronization, the Axitinib suspended in 5.7% ethanol/94.3% WFIwas filtered through a 0.2 um vacuum filter (Thermo Scientific) andrinsed 3× with 100 mL of WFI. After filtration, Axitinib powder wascollected from the filter using a spatula, and vacuum dried overnight ina 10 mL serum vial to remove all excess solvent.

Particle Size Analysis

Particle size was analyzed using a Beckman Coulter LS 120 Particle SizeAnalyzer. Samples were sonicated for 15 minutes in Deionized waterbefore analysis. On average the particle size distribution is such:d10=0.773 um, d50=2.605 um, d90=6.535 um.

Example 10 Illustrated Description of Processes Used to Make CoilingBi-Polymeric Fibers

1. Formulate PEG solutions (aqueous or organic), and transfer intosyringes (PEG Ester solution in one syringe, FIG. 15B PEG Amine solutionin a separate syringe. Can also include an Active Pharmaceutical Agent(API), either in a third syringe or in one or both of the PEG syringes.

2. Mix contents of each syringe together and inject into small IDtubing, (in this Example, 0.51 mm ID).

3. Allow to crosslink, then dry inside the tubing (may use heat, inertgas sweep, vacuum, or a combination of any of these) to form a fiber,see FIG. 15A.

4. Remove Dried fiber from the tubing, FIG. 15B.

5. Stretch/neck the dry fiber. Fiber holds the thinner, elongated shape,FIGS. 15C-15E, with stretched fiber shown in FIG. 15F.

6. Thread fiber into small inner diameter polyethylene tube, with endsof fiber exposed outside of the tube.

7. Wrap tube and fiber around a curved surface. Fix both ends of thefiber such that it is held taught around the inner surface of the tubingcurve.

8. Prepare hydrogel precursor solutions and mix (same process as Steps 1and 2). Inject the hydrogel into the polyethylene tubing containing thestretched fiber.

9. Allow to crosslink, then dry inside the tubing (same methods as Step3).

10. Once dry, remove from tubing and cut to desired length.

Example 11 Alternative Process for Necking, Coating, and Drying CoilingBiPolymer Fibers

1. Cast hydrogel or organogel and dry as previously disclosed or bysimilar method. Maximum length of strand cast will be dependent on therate of crosslinking (gel time) vs tube length and inner diameter.

2. Fixture or clamp tubing to hold straight. This may be done using ablock that is as long, or longer than the tubing length, with asemi-circular grove through the length of the block that snugly fitsaround the tubing, or another similar method. Cut away end of tubing andgrasp dried strand.

3. Pull out to expose the fiber end from the tubing. Thread the end ofthe fiber through the looped/hooked end of a ligature, wire, or othersimilar device. Use this device to thread the fiber through a die orother tool to draw down the diameter while stretching the fiber.

-   -   a. Tool design to uniformly neck the fiber without imparting        enough drag due to friction to cause sufficient resistance to        tear the fiber. Gradual taper, smooth surfaces in contact with        fiber.

4. Continue to thread necked fiber into the tubing that will be used tocast the coating gel.

-   -   a. Tubing may be continuous length, or a series of shorter        segments. Gel will be cast into each individual length of        tubing, and segment length will be determined by the gel time of        the coating gel.

5. Remove ligature/wire device and connect the necked fiber to a largecylindrical drum. Rotate the drum to uptake the tubing and necked fiberonto the drum surface. Once completely wrapped around the drum, connectthe free end to the drum, holding the fiber wrapped tightly and taut.

-   -   a. Additional support of the tubing may be required, and can use        grooves formed into the surface of the drum, features to        clamp/hold the tubing against the drum, or other means.

6. Cast gel into tube segment(s). Dry while held taut onto the drum.

Example 12 Fiber Component Formed From Organogel

Bipolymer fibers formed from organogel (Example 3A or 3B) were furthertested for degradation and found to last longer in vivo before fulldegradation compared to the same compositions made in aqueous solution.The difference in persistence was enough to provide for effectivelycomplete dissolution of the aqueous-based polymer while theorganogel-derived hydrogel was still persistent.

Example 13 Use of Multiple Fibers Yields Faster Coiling Rate FiberFormation

Syringe 1: Targeted 40 mg of Polyethylene glycol (PEG), MW=20 KDa, 4arms (initiated with pentaerythritol), each arm end-capped withsuccinimidyl azelate (4a20k PEG SAZ) was weighed into a 1 mL PE syringeand dissolved in 360 mg of Dimethyl carbonate.

Syringe 2: Targeted 20 mg of Polyethylene glycol (PEG), MW=20 KDa, 8arms (initiated with hexaglycerol), each arm end-capped with an amine(8a20k PEG NH₂) was weighed into a 1 mL PE syringe and dissolved in 380mg of Dimethyl carbonate.

The contents of syringe 1 and syringe 2 were mixed and injected intopolyurethane tubing, each approximately 5 m long, having an innerdiameter of approximately 0.20 mm using a 31 G cannula. After gelationwas confirmed, each tube was then transferred into a 37° C. chamberunder a nitrogen sweep to dry for about 1 day. Each dried strand segmentof approximately 10 cm length was gently stretched by manually pullinggently on both ends, causing necking, to form an oriented fiber alongits full length. The final draw ratio was 5.

Each necked fiber (done with 1, 2, 3, 5, 7, or 9 fibers) was pulled intoa length of polyurethane tubing having an inner diameter ofapproximately 0.508 mm and the tubing was cut to 25 cm in length. A 2.5cm segment of each fiber remained exposed outside of each end of thetubing, and each end of the taut fiber was taped to the side of a 140 mmaluminum weigh boat using laboratory tape. The curvature of the weighboat was used to maintain the fiber's tautness against the inside wallof the tube.

Second Layer with Drug

Syringe 3: Targeted 16.8 mg of 8a20k PEG NH₂ was weighed into a 1 mL PEsyringe and dissolved in 130.25 mg of the Dimethyl carbonate.

Syringe 4: Targeted 8.0 mg of Polyethylene glycol (PEG), MW=15 KDa, 8arms (initiated with pentaerythritol), each arm end-capped withsuccimimidyl adipate (8a15k PEG SAP) and 7.1 mg of Polyethylene glycol(PEG), MW=20 KDa, 4 arms (initiated with pentaerythritol), each armend-capped with succimimidyl adipate (4a20k PEG SAP) were each weighedinto the same 1 mL PE syringe and dissolved in 131.9 mg of Dimethylcarbonate.

Spray-dried powder: Bovine IgG (Sigma Aldrich) was spray-dried using aBuchi B290 spray-drier to form particles with a median diameter ofapproximately 7.5 microns. The spray-dried powder composition wasapproximately 70% IgG, 28% sucrose and 2% buffer salts.

Syringe 5: Targeted 106 mg of spray-dried Bovine IgG was weighed into acapped syringe.

The contents of the syringes 3 and 5 were mixed vigorously using a luerto luer connector. The contents of these syringes were thenquantitatively transferred into one syringe, capped, and sonicated for15 minutes to disperse all agglomerates under cold conditions (8-15°C.). The contents of this syringe were then mixed with syringe 4 andinjected into one end of the polyurethane tubing containing the fiber,filling the lumen to coat the fiber while the fiber was held in tension,and the coating was allowed to gel. After gelation of the coating, thesample, still attached to the weight boat, was transferred into the 37°C. chamber under a nitrogen sweep, where it remained for 5 days. Thetubing was cut to approximately 2.54 cm segments and the fiber carefullyremoved from each segment. The diameter of coated fiber ranged from 0.31to 0.35 mm.

Coil rate determined by injecting 2.54 cm segment into 37° C. 2.0%sodium hyaluronate (MW=850 KDa) (HA) solution in PBS over a 2 secondperiod and the time was recorded for the segment to achieve a coiledshape. Results are shown in FIG. 19.

Example 14 Use of Larger Fibers Yields Faster Coiling Rate FiberFormation

Syringe 1: Targeted 40 mg of Polyethylene glycol (PEG), MW=20 KDa, 4arms (initiated with pentaerythritol), each arm end-capped withsuccinimidyl azelate (4a20k PEG SAZ) was weighed into a 1 mL PE syringeand dissolved in 360 mg of Dimethyl carbonate.

Syringe 2: Targeted 20 mg of Polyethylene glycol (PEG), MW=20 KDa, 8arms (initiated with hexaglycerol), each arm end-capped with an amine(8a20k PEG NH₂) was weighed into a 1 mL PE syringe and dissolved in 380mg of Dimethyl carbonate.

The contents of syringe 1 and syringe 2 were mixed and injected into avolume appropriate length of polyurethane tubing, having an innerdiameters of each 0.203, 0.35, and 0.508 mm using an appropriately sizedcannula. After gelation was confirmed, each tube was then transferredinto a 37° C. chamber under a nitrogen sweep to dry for about 2 days.Each dried strand segment of approximately 10 cm length was gentlystretched by manually pulling gently on both ends, causing necking, toform an oriented fiber along its full length. The final draw ratio was5.

A necked fiber was pulled into a length of polyurethane tubing having aninner diameter of approximately 0.508 mm and the tubing was cut to 25 cmin length. A 2.5 cm segment of each fiber remained exposed outside ofeach end of the tubing, and each end of the taut fiber was taped to theside of a 140 mm aluminum weigh boat using laboratory tape. Thecurvature of the weigh boat was used to maintain the fiber's tautnessagainst the inside wall of the tube.

Second Layer with Drug

Syringe 3: Targeted 16.0 mg of 8a20k PEG NH₂ was weighed into a 1 mL PEsyringe and dissolved in 149.5 mg of the Dimethyl carbonate.

Syringe 4: Targeted 9.0 mg of Polyethylene glycol (PEG), MW=15 KDa, 8arms (initiated with pentaerythritol), each arm end-capped withsuccimimidyl adipate (8a15k PEG SAP) and 8.0 mg of Polyethylene glycol(PEG), MW=20 KDa, 4 arms (initiated with pentaerythritol), each armend-capped with succimimidyl adipate (4a20k PEG SAP) were each weighedinto the same 1 mL PE syringe and dissolved in 148.5 mg of Dimethylcarbonate.

Syringe 5: Targeted 119 mg of spray dried Bovine IgG was weighed into acapped syringe.

The contents of the syringes 3 and 5 were mixed vigorously using a luerto luer connector. The contents of these syringes were thenquantitatively transferred into one syringe, capped, and sonicated for15 minutes to disperse all agglomerates under cold conditions (8-15°C.). The contents of this syringe were then mixed with syringe 4 andinjected into one end of the polyurethane tubing containing the fiber,filling the lumen to coat the fiber while the fiber was held in tension,and the coating was allowed to gel. After gelation of the coating, thesample, still attached to the weight boat, was transferred into the 37°C. chamber under a nitrogen sweep, where it remained for 4 days. Thetubing was cut to approximately 2.54 cm segments and the fiber carefullyremoved from each segment. The diameter of coated fibers were 0.33 mm.

Coil rate determined by injecting 2.54 cm segment into 37° C. 2.0%sodium hyaluronate (MW=850 KDa) (HA) solution in PBS over a 2 secondperiod and the time was recorded for the segment to achieve a coiledshape. Results are shown in FIG. 20.

Example 15 Multiple Segments That Entangle Upon Hydration InducedCoiling Fiber Formation

Syringe 1: Targeted 45 mg of Polyethylene glycol (PEG), MW=20 KDa, 4arms (initiated with pentaerythritol), each arm end-capped withsuccinimidyl azelate (4a20k PEG SAZ) was weighed into a 1 mL PE syringeand dissolved in 405 mg of Dimethyl carbonate.

Syringe 2: Targeted 22.5 mg of Polyethylene glycol (PEG), MW=20 KDa, 8arms (initiated with hexaglycerol), each arm end-capped with an amine(8a20k PEG NH₂) was weighed into a 1 mL PE syringe and dissolved in427.5 mg of Dimethyl carbonate.

The contents of syringe 1 and syringe 2 were mixed and injected intopolyurethane tubing, each approximately 5 m long, having an innerdiameter of approximately 0.35 mm using a 27 G cannula. After gelationwas confirmed, each tube was then transferred into a 37° C. chamberunder a nitrogen sweep to dry for about 2 days. Each dried strandsegment of approximately 15 cm length was gently stretched by manuallypulling gently on both ends, causing necking, to form an oriented fiberalong its full length. The final draw ratio was 5.

Two necked fibers were pulled into a length of polyurethane tubinghaving an inner diameter of approximately 0.508 mm and the tubing wascut to 25 cm in length. A 2.5 cm segment of each fiber remained exposedoutside of each end of the tubing, and each end of the taut fiber wastaped to the side of a 140 mm aluminum weigh boat using laboratory tape.The curvature of the weigh boat was used to maintain the fiber'stautness against the inside wall of the tube.

Second Layer with Drug

Syringe 3: Targeted 14.25 mg of 8a20k PEG NH₂ was weighed into a 1 mL PEsyringe and dissolved in 132.8 mg of the Dimethyl carbonate.

Syringe 4: Targeted 8.0 mg of Polyethylene glycol (PEG), MW=15 KDa, 8arms (initiated with pentaerythritol), each arm end-capped withsuccimimidyl adipate (8a15k PEG SAP) and 7.1 mg of Polyethylene glycol(PEG), MW=20 KDa, 4 arms (initiated with pentaerythritol), each armend-capped with succimimidyl adipate (4a20k PEG SAP) were each weighedinto the same 1 mL PE syringe and dissolved in 131.9 mg of Dimethylcarbonate.

Syringe 5: Targeted 106 mg of spray dried Bovine IgG was weighed into acapped syringe.

The contents of the syringes 3 and 5 were mixed vigorously using a luerto luer connector. The contents of these syringes were thenquantitatively transferred into one syringe, capped, and sonicated for15 minutes to disperse all agglomerates under cold conditions (8-15°C.). The contents of this syringe were then mixed with syringe 4 andinjected into one end of the polyurethane tubing containing the fiber,filling the lumen to coat the fiber while the fiber was held in tension,and the coating was allowed to gel. After gelation of the coating, thesample, still attached to the weight boat, was transferred into the 37°C. chamber under a nitrogen sweep, where it remained for 4 days. Thetubing was cut to either 15 or 12 mm segments at either 30, 45, 52.5, or60° angles (0° angle would be a perpendicular cut along the tubing). Thediameter of coated fiber ranged from 0.33 to 0.35 mm.

Fiber injection distance, the maximum distance the fiber couldpotentially reach during injection, was evaluated by injecting varioussegment numbers and lengths totaling to 60 mm that are parallel loadedinto a needle into 37° C. 2.0% sodium hyaluronate (MW=850 KDa) (HA)solution in PBS and recording videos. A hoop of wire is used toapproximate the OD of a human eye as a visualization aid for some of theinjections. Results are shown in FIG. 21.

Example 16 Angle Cut of Multiple Segments Fiber Formation

Syringe 1: Targeted 45 mg of Polyethylene glycol (PEG), MW=20 KDa, 4arms (initiated with pentaerythritol), each arm end-capped withsuccinimidyl azelate (4a20k PEG SAZ) was weighed into a 1 mL PE syringeand dissolved in 405 mg of Dimethyl carbonate.

Syringe 2: Targeted 22.5 mg of Polyethylene glycol (PEG), MW=20 KDa, 8arms (initiated with hexaglycerol), each arm end-capped with an amine(8a20k PEG NH₂) was weighed into a 1 mL PE syringe and dissolved in427.5 mg of Dimethyl carbonate.

The contents of syringe 1 and syringe 2 were mixed and injected intopolyurethane tubing, each approximately 5 m long, having an innerdiameter of approximately 0.35 mm using a 27 G cannula. After gelationwas confirmed, each tube was then transferred into a 37° C. chamberunder a nitrogen sweep to dry for about 2 days. Each dried strandsegment of approximately 15 cm length was gently stretched by manuallypulling gently on both ends, causing necking, to form an oriented fiberalong its full length. The final draw ratio was 5.

Two necked fibers were pulled into a length of polyurethane tubinghaving an inner diameter of approximately 0.508 mm and the tubing wascut to 25 cm in length. A 2.5 cm segment of each fiber remained exposedoutside of each end of the tubing, and each end of the taut fiber wastaped to the side of a 140 mm aluminum weigh boat using laboratory tape.The curvature of the weigh boat was used to maintain the fiber'stautness against the inside wall of the tube.

Second Layer with Drug

Syringe 3: Targeted 16.0 mg of 8a20k PEG NH₂ was weighed into a 1 mL PEsyringe and dissolved in 149.5 mg of the Dimethyl carbonate.

Syringe 4: Targeted 9.0 mg of Polyethylene glycol (PEG), MW=15 KDa, 8arms (initiated with pentaerythritol), each arm end-capped withsuccimimidyl adipate (8a15k PEG SAP) and 8.0 mg of Polyethylene glycol(PEG), MW=20 KDa, 4 arms (initiated with pentaerythritol), each armend-capped with succimimidyl adipate (4a20k PEG SAP) were each weighedinto the same 1 mL PE syringe and dissolved in 148.5 mg of Dimethylcarbonate.

Syringe 5: Targeted 119 mg of spray dried Bovine IgG was weighed into acapped syringe.

The contents of the syringes 3 and 5 were mixed vigorously using a luerto luer connector. The contents of these syringes were thenquantitatively transferred into one syringe, capped, and sonicated for15 minutes to disperse all agglomerates under cold conditions (8-15°C.). The contents of this syringe were then mixed with syringe 4 andinjected into one end of the polyurethane tubing containing the fiber,filling the lumen to coat the fiber while the fiber was held in tension,and the coating was allowed to gel. After gelation of the coating, thesample, still attached to the weight boat, was transferred into the 37°C. chamber under a nitrogen sweep, where it remained for 5 days. Thetubing was cut to either 15 or 12 mm segments at either 30, 45, 52.5, or60° angles (0° angle would be a perpendicular cut along the tubing). Thediameter of coated fiber ranged from 0.33 to 0.35 mm.

Fiber training, the phenomenon where one segment pushes its precedingsegment during injection increasing the maximum distance a fiber travelsfrom the injection needle tip, was evaluated by injecting various lengthsegments parallel loaded into a needle into 37 ° C. 2.0% sodiumhyaluronate (MW=850 KDa) (HA) solution in PBS and recording videos. Ahoop of wire is used to approximate the OD of a human eye as avisualization aid. Results are shown in FIG. 22.

Example 17 Example: Necked and Coiled Fibers Formulation and In VivoDelivery of Axitinib Formulation 1 Necked Fiber Preparation BufferPreparation

Buffer 1: 600.0 mg of Sodium phosphate dibasic was weighed into a 25 mLvolumetric flask, and brought to volume with deionized water.Preparation was then stirred until dibasic appears to be fully insolution. The result is a 24 mg/mL dibasic solution.

Buffer 2: 225.0 mg of Sodium phosphate monobasic was weighed into a 25mL volumetric flask, and brought to volume with deionized water.Preparation was then stirred until monobasic appears to be fully insolution. The result is a 9 mg/mL monobasic solution.

Fiber Casting with Drug Loaded Hydrogel

Syringe 3: Polyethylene glycol (PEG), MW=20 KDa, 8 arms, each armend-capped with amine (8a20k PEG NH₂, 12.0 mg) was weighed into a 1 mLglass syringe (Cadence) and dissolved in 228.0 μL of Buffer 1.

Syringe 4: Polyethylene glycol (PEG), MW=20KDa, 4 arms (initiated withpentaerythritol), each arm end-capped with succimimidyl azelate (4a20kPEG SAZ, 24.0 mg) was weighed into a 1 mL glass syringe and dissolved in216.0 μL of Buffer 2.

Syringe 5: 53.3 mg of Shilpa manufactured Axitinib was weighed into acapped 1 mL glass syringe.

The contents of the syringes 3 and 5 were mixed vigorously using a luerto luer connector. The contents of these syringes were thenquantitatively transferred into one syringe, capped, and sonicated for 5minutes to disperse all agglomerates. The contents of this syringe werethen mixed with syringe 4 and injected into one end of a 4 ft segmentpolyurethane tubing with an inner diameter of 0.76 mm with a 21 G 1.5″needle (Becton Dickinson) Gel time was approximately 2.5 minutes.Segments were then transferred to a saturated aqueous environment tocure for approximately 60 minutes. After curing, segments were cut to 12inches and placed in a nitrogen sweep at room temperature and allowed todry for about 48 hours. Once dry, fibers were removed from the tubing.Each dried strand was gently stretched by manually pulling gently onboth ends, causing necking, to form an oriented fiber along its fulllength (initial length 254 mm, final length 762 mm). The final drawratio was 3.0.

Formulation 2 Coiled Fiber Preparation Buffer Preparation

Prebuffer 1: 600.0 mg of Sodium phosphate dibasic was dissolved in 25 mLdeionized water.

Prebuffer 2: 225.0 mg of Sodium phosphate monobasic was dissolved in 25mL deionized water.

Fiber Element 1 (E1) Formation of a Necked Fiber for Use as the FiberBackbone

Syringe 1: The precursor polymer from Example 1 (4a50kPEG AZA, 30.0 mg)was weighed into a 1 mL, polyethylene (PE) syringe (BD) and dissolved in145.1 μL of dimethyl carbonate (DMC).

Syringe 2: Polyethylene glycol (PEG), MW=20 KDa, 4 arms, each armend-capped with succinimidyl carbonate (4a20k PEG SC, 12.0 mg) wasweighed into a 1 mL, PE syringe (BD) and dissolved in 163.1 μL of DMC.

The contents of syringe 1 and syringe 2 were mixed and injected into one46 cm length of polyurethane tubing (80 A durometer), having an innerdiameter of approximately 0.20 mm using a 30 G needle. After gelationwas confirmed (about 15 seconds), the tubing containing the gel was cutinto 101 mm segments and each segment was then transferred into achamber holding a saturated dimethyl chloride (DMC) environment forabout 15 minutes. Segments were transferred to a 37° C. chamber under anitrogen sweep to dry for about 24 hours. Each dried strand was gentlystretched by manually pulling gently on both ends, causing necking, toform an oriented fiber along its full length (initial length 26 mm,final length 164 mm). The final draw ratio was 6.3.

The effective draw ratio was reduced by shrinking the necked fiber usingheat to melt the PEG crystalline regions. To do this step, the 164 mmnecked fiber was inserted into a length of PTFE tubing having an innerdiameter of approximately 0.802 mm and a length of 150 mm, and was thenadhered to the outer curved surface of an aluminum weigh boat to keepthe ends of the fiber firmly secured at a length of 164 mm, leavingslack in the dry necked fiber between the fixation points on either sideof the tubing. The entire weigh boat was then placed into a 40° C.chamber under nitrogen sweep to shrink back the necked fiber using heatto the predetermined length of 164 mm. Once the fiber was taught at alength of 164 mm (overnight), the weigh boat was removed from the ovenfor the next step.

Fiber Element 2 (E2) Coating with Drug Loaded Hydrogel

Syringe 3: Polyethylene glycol (PEG), MW=20 KDa, 8 arms, each armend-capped with amine (8a20k PEG NH₂, 12.0 mg) was weighed into a 1 mLglass syringe (Cadence) and dissolved in 228.0 μL of Prebuffer 1.

Syringe 4: Polyethylene glycol (PEG), MW=20 KDa, 4 arms (initiated withpentaerythritol), each arm end-capped with succimimidyl azelate (4a20kPEG SAZ, 24.0 mg) was weighed into a 1 mL glass syringe and dissolved in216.0 μL of Prebuffer 2.

Syringe 5: 53.3 mg of axitinib was weighed into a capped 1 mL glasssyringe.

The contents of the syringes 3 and 5 were mixed vigorously using a luerto luer connector. The contents of these syringes were transferred intoone syringe, capped, and placed in a sonication bath for 5 minutes todisperse agglomerated particles. The contents of this syringe were thenmixed with syringe 4 and injected into the PTFE tubing containing thefiber, filling the lumen to coat the E1 fiber while the fiber was stillheld in tension, and the coating was allowed to gel (gel time ˜2.5 min).After gelation, the sample, still attached to the weight boat, wastransferred into a chamber holding a saturated water environment forabout 70 minutes. Then the sample while still attached to the weightboat was transferred into the 37° C. chamber under a nitrogen sweep forapproximately 7 days to dry.

Fiber Injection

Fibers were cut to 20 mm lengths and loaded into a 27 G UTW 1″ needle(JBP). The needles were then luer locked to a 50 uL Hamilton glasssyringe with a 0.010″ diameter push rod (2.0″ long) in the barrel. Thispush rod would successfully deploy the fiber as the plunger wasdepressed in the barrel of the syringe. The fibers would then eithercoil upon hydration (Coiled fiber formulation 2), or shrink and fatten(Necked Fiber formulation 1).

Study Design

The tolerability, pharmacokinetics, and pharmacodynamics of theformulations from examples 1 and 2 were evaluated in Dutch beltedrabbits through 6 months. 112 eyes of naive Dutch belted rabbits (n=66)were bilaterally dosed with either a necked fiber or a coiled fiber andwere sacrificed at 1, 3 and 6 months to test for biocompatibility orpharmacokinetics.

In Vivo Drug Release

Drug release from the fibers over time in vivo was characterized overtime by two different methods. The first method was qualitative innature. Infrared fundus images were collected bi-weekly over a 6 monthperiod, with the intent of imaging the coiled fiber in the vitreous.Over time, the fiber becomes more translucent and porous, indicatingdrug solubilizing out of the hydrogel matrix and being delivered to thetarget tissues. Additionally, the hydrogel depots themselves begin toshrink in size as the hydrogel degraded and releases drug. Drug releaseover time was also characterized in a more quantitative method byanalyzing the explanted depots at terminal time points (1, 3 and 6months) by LC-MS/MS (liquid chromatography with dual mass spectroscopy).The results show a declining quantity of drug in the depots over timethroughout the study.

In Vivo Drug Delivery

Drug delivery to the tissues over time was captured quantitatively byperforming tissue concentration analysis at several time points over the6 month period (1, 3 and 6 months). Eyes at each time point wereenucleated and flash frozen using liquid nitrogen. While frozen, eyeswere dissected; the vitreous humor was removed and collected, then theretina and choroid were collected in that order. The vitreous humor wasthen allowed to thaw, and the fiber depots were removed from the sample.All tissues were then homogenized and the drug was extracted using amethanol media. Samples were tested against a stock standard curve byLC-MS/MS using stock axitinib. This analysis showed an increasingconcentration of axitinib in these target tissues (>313 ng drug /g oftarget tissues at all time points) over the duration of the 6 monthstudy. Based on the half-life and clearance rates of axitinib, thesetissue concentrations could have only been possible with the constantand sustained delivery of axitinib from the delivery device.

TABLE 17-1 Drug remaining in explanted depots by LC-MS/MS from bothformulations at 1, 3, and 6 months showing a progression of drug releasefrom the depots over time 1 month 3 month 6 month Axitinib remaining inNecked (μg) 238 67 55 Axitinib remaining in Coiled (μg) 290 120 110

Table 17-2 showing the ng axitinib/g tissue and and subsequentcalculated values of the compiled pharmokinetic (PK) data for theOTX-TKI Necked Fiber (Formulation 1). These values over time show anincreasing concentration of axitinib in the tissues thus demonstratingcontinued release of drug from the fiber depot over the 6 month period.The amount of axitinib, ng, per gram, of tissue, g, is shown for each ofthe choroid, retina, vitrous humor (VH), remaining in the vehicle(depot), aqueous humor (AH), and plasma are listed. The concentration inthe retina is also listed as a multiple of the IC₅₀ for effectiveness(half of maximal effectiveness), e.g., 6934x the required IC₅₀ at week4; this data is also expressed in log format with the standarddeviation.

Table 17-3 showing the ng axitinib/g tissue and subsequent calculatedvalues of the compiled PK data for the OTX-TKI Coiled Fiber (Formulation2). These values over time show an increasing concentration of axitinibin the tissues thus demonstrating continued release of drug from thefiber depot over the 6 month period. Abbreviations as described above.

Many embodiments have been set forth herein. In general, components ofthe embodiments may be mixed-and-matched with each other as guided forthe need to make functional embodiments. For instance, aspect ratios,gauge sizes, diameters, coil times, precursors, functional groups,hydrogel structures, degradation times, relative degradation times,swelling and elongation coefficients, therapeutic agents, agent loadingprocesses, weakening techniques, necking techniques, bipolymer andmultipolymer vehicle designs, sites of delivery, delivery methods, andother features set forth herein may be independently chosen as guided bythis Application and the skill of the art to make and use theembodiments set forth herein. Patent application, patents, journalarticles, and publications set forth herein are hereby incorporated byreference herein; in case of conflict, the instant specificationcontrols.

Further Disclosure

1. A method of drug delivery comprising introducing a solidshape-changing vehicle containing a drug into a tissue, the vehiclechanging shape in response to a physiological fluid of the tissue andproviding a controlled release of a therapeutic agent.

2. The method of 1 wherein the vehicle also changes in volume inresponse to a physiological fluid of the tissue. The method of 1 whereinthe vehicle has a first effective gauge that changes to a largereffective gauge after changing shape in response to the physiologicalfluid.

3. The method of 1 or 2 wherein the vehicle, in response to thephysiological fluid, decreases in length, increases in width, andincreases in volume.

4. The method of any of 1-3 wherein the vehicle is passed through anopening and placed at the tissue, with the change in shape and a volumechange of the vehicle preventing expulsion of the vehicle through theopening.

5. The method of 4 wherein the opening is a puncture, a puncture madewith a needle, an entry wound, or a pre-existing passage.

6. The method of any of 1-5 wherein a shape and/or a volume change ofthe vehicle reduces the tendency of the vehicle to migrate from the sitewhere it is initially placed compared to the shape and dimensions of thevehicle before the shape change.

7. The method of any of 1-6 wherein the vehicle, before introductioninto the tissue, is a rod having an aspect ratio of at least 1:10.

8. The method of 7 wherein the rod is straight prior to introductioninto the tissue.

9. The method of any of 1-8 wherein the vehicle curls into a curvedshape in response to the fluid.

10. The method of any of 1-5 wherein the vehicle is a rod that, inresponse to the fluid, coils.

11. The method of any of 1-6 wherein the vehicle, before theintroduction, is passable through a hypodermic needle (for example, 27gauge) of at least 5 mm in length.

12. The method of any of 1-11 wherein the vehicle is biodegradable.

13. The method of 12 wherein the vehicle is biodegradable as a result ofthe spontaneous hydrolysis of water-labile bonds upon exposure to thephysiological fluid.

14. The method of 12 wherein the vehicle does not have water-labilebonds and is biodegradable in response to local cellular and/orenzymatic activity at the site of implantation.

15. The method of any of 1-14 wherein the vehicle is a xerogel thatforms a hydrogel when exposed to the physiological fluid. 16. The methodof any of 1-15 wherein the vehicle comprises a weakened area thatprovides for the vehicle to curve when exposed to the fluid.

17. The method of 16 wherein the weakened area comprises a notch that isa result of a stretching process or created with tools for cutting orremoving material to make the weakened area(s).

18. The method of any of 1-17 wherein the vehicle comprises a first anda second material that are joined together.

19. The method of 14 wherein the first material has a first coefficientof elongation in physiological solution and the second material has asecond coefficient of elongation in physiological solution, with firstand second coefficients of elongation being different.

20. The method of 19 wherein the first material has a first coefficientof swelling in physiological solution and the second material has asecond coefficient of swelling in physiological solution, with first andsecond coefficients of swelling being different.

21. The method of 19 or 20 wherein the vehicle comprises a layer of thesecond material on the first material.

22. The method of 19 or 20 wherein the vehicle comprises a layer of thesecond material that surrounds the first material.

23. The method of 22 wherein the first material comprises at least onerod or at least one strand, with the rod or the strand being surroundedby the first material.

24. The method of 23 wherein the at least one rod or the at least onestand have a coefficient of elongation that is not the same as thecoefficient of elongation. As a result, shape changes upon exposure tophysiological fluid are provided, including complex shape changes. Acoefficient of elongation may be independently selected for each of therods or strands.

25. The method of claim 24 wherein the at least one rod or the at leastone strand surrounded by the second material have a rate of degradationthat is not the same a rate of degradation of the second material. As aresult, further shape changes may be provided during the degradationprocess.

26. The method of any of 18-25 wherein the first material is a rodencapsulated by the first material.

27. The method of any of 19-25 wherein the first coefficient (elongationor swelling) and the second coefficient (elongation or swelling) areindependently selected to be less than one or more than one.

28. The method of any of 18-27 wherein the first material or the secondmaterial also encapsulates or otherwise holds a drug.

29. The method of any of 18-28 wherein the first material and/or thesecond material has a coefficient of elongation and/or a coefficient ofswelling that ranges from 0.05 to 0.5.

30. The method of any of 18-28 wherein the first coefficient (elongationor swelling) and the second coefficient (elongation or swelling) areindependently selected to be in a range from 0.01 to 100.

31. The method of any of 18-28 wherein the first material and the secondmaterial degrade at different rates, or one of the materials isnon-degradable and the second material is degradable.

32. The method of 31 wherein the first material and the second materialare chosen to degrade at a rate independently selected from 2 days to 5years. Artisans will immediately appreciate that all ranges and valuesbetween the explicitly stated bounds are contemplated, with, e.g., anyof the following being available as an upper or lower limit: 3, 4, 5, 6,7 days, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 52 weeks, 1,1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5 years.

33. The method of 31 wherein the first material degrades at a rate thatis from 1.5× to 10× faster than the second material or vice versa.

34. The method of claim any of 31-33 wherein the differentialdegradation rates provide for the vehicle to maintain an initial shape(e.g., coil shape) for a period of time between 2-365 days (all rangescontemplated). This property provides for the shape to be maintaineduntil advanced stages of the degradation process.

35. The method of any of 31-33 wherein the differential degradationrates determine the ability to unfurl a coil or other compact shape atparticular stages of the degradation process.

36. The method of claim 33 wherein the first material comprises multiplehydrogels (e.g., rods, strands) surrounded by the second material

37. The method of claim 36 wherein the multiple strands surrounded bythe second material have a range coefficients of elongation such thatcomplex shape changes upon exposure to physiological fluid can beengineered.

38. The method of claim 36 wherein the multiple strands surrounded bythe second material have a range of hydrolytic or enzymatic degradationtimes to control shape changes during the degradation process.

39. The method of any of 1-38 wherein the therapeutic agent has asolubility in aqueous solution of no more than 10 micrograms permilliliter.

40. The method of any of 1-38 wherein the therapeutic agent is a proteinwith MW greater than 1000 Da.

41. The method of any of 1-38 wherein the therapeutic agent isencapsulated in a microparticle.

42. The method of any of 1-41 wherein the therapeutic agent comprises ananti-angiogenic agent or other agent set forth herein.

43. The method of any of 1-41 wherein the therapeutic agent comprises atyrosine kinase inhibitor.

44. The method of any of 1-41 wherein the therapeutic agent comprises ananti-VEGF protein or antibody or aptamer.

45. The method of any of 1-41 wherein the therapeutic agent comprises ananti-PDGF protein or antibody or aptamer.

46. The method of any of 1-41 wherein the therapeutic agent comprises ananti-Ang2 protein or antibody or aptamer.

47. The method of any of 1-46 wherein the tissue is a potential spacethat is natural or is created for deposition of the vehicle.

48. The method of any of 1-46 wherein the vehicle is introduced at, in,or near an eye, into the conjunctiva, on the cornea, on a sclera, insidea sclera, on an interior wall of the eye, intraocular, in the vitreoushumor, on a retina, near a retina but not touching a retina, a distanceof 1 to 2000 microns from a retina, suprachoroidal, in the choroidal, ina potential space, in a lumen artificially (by a user, with a tool)created to receive the vehicle, in a chamber of an eye, in the posteriorchamber, in contact with vitreous humor, in the hyaline canal, or acombination thereof.

49. The method of any of 1-46 wherein the vehicle is introduced at, in,or near a vitreous humor or aqueous humor, Canaliculus, ampulla,Paranasal sinus, Joint capsules (e.g. knee, hip, etc.), Lumpectomy site,Biopsy site, Tumor core, Ear canal, Vaginal, Bladder, Esophageal,Bronchial, Abscesses, e.g. Dental, AV malformation sites, Vascularaneurysms or dissections, potential spaces, artificially created spacesor potential spaces, pessary, buccal, anal, uretheral, nasal, breast,iatrogenic, cancer, organs, luminal spaces, natural lumen, vascular,aneurysm.

50. The method of any of claims 1-49 wherein the vehicle is a rod thathas an end that is cut at an angle of 30-60 degrees relative to aperpendicular cross-section.

51. The method of 50 further comprising introducing a plurality of thevehicles through a single needle or catheter.

52. The method of 51 wherein the vehicles contact each other in thesingle needle or catheter and are released into the site where theyindependently change shape, e.g., coil or form helices.

53. A device for drug delivery comprising a therapeutic agent disposedin a vehicle that changes shape in response to a physiological fluid andprovides a controlled release of a therapeutic agent.

54. The device of 53 wherein the vehicle comprises a rod with an aspectratio of at least 1:10.

55. The device of 53 or 54 wherein the vehicle has a first effectivegauge that changes to a larger effective gauge after changing shape inresponse to the physiological fluid.

56. The device of any of 50-55 wherein the vehicle in response to thephysiological fluid, decreases in length and increases in width.

57. The device of any of 50-56 wherein the device, before introductioninto the eye, is a rod having an aspect ratio of at least 1:10.

58. The device of any of 50-33 wherein the device curls into a curvedshape response to the fluid.

59. The device of any of 50-34 wherein the vehicle is a rod that, inresponse to the fluid, coils.

60. The device of any of 50-35 wherein the vehicle, before theintroduction, is passable through a 27 gauge thin wall needle of atleast 5 mm in length.

61. The device of any of 50-36 wherein the vehicle is biodegradable.

62. The device of 61 wherein the vehicle is biodegradable as a result ofthe spontaneous hydrolysis of water-labile bonds upon exposure to thephysiological fluid.

63. The device of 61 wherein the vehicle does not have water-labilebonds and is biodegradable in response to local cellular and/orenzymatic activity at the site of implantation.

64. The device of any of 50-63 wherein the vehicle is a xerogel thatforms a hydrogel when exposed to the physiological fluid.

65. The device of any of 50-64 wherein the vehicle comprises a weakenedarea that provides for the vehicle to curve when exposed to the fluid.

66. The device of 65 wherein the weakened area comprises a score, anotch, or a tear, with any of the same being a result of a stretchingprocess or created with tools for cutting or removing material to makethe weakened area(s).

67. The device of any of 50-66 wherein the vehicle comprises a first anda second material that are joined together.

68. The device of 67 wherein the first material has a first coefficientof elongation in physiological solution and the second material has asecond coefficient of elongation in physiological solution, with firstand second coefficients of elongation being different.

69. The device of 67 wherein the first material has a first coefficientof swelling in physiological solution and the second material has asecond coefficient of swelling in physiological solution, with first andsecond coefficients of swelling being different.

70. The device of 68 or 69 wherein the vehicle comprises a layer of thefirst material on the second material.

71. The device of 68 or 69 wherein the vehicle comprises a layer of thesecond material that surrounds the first material.

72. The device of 71 wherein the first material is a rod encapsulated bythe first material.

73. The device of any of 68-72 wherein the first coefficient (elongationor swelling) and the second coefficient (elongation or swelling) areindependently selected to be less than one or more than one.

74. The device of any of 68-72 wherein the first material and/or secondmaterial has a coefficient of change that ranges from 0.05 to 0.5.

75. The device of any of 68-72 wherein the first coefficient (elongationor swelling) and the second coefficient (elongation or swelling) areindependently selected to be in a range from 0.01 to 100.

76. The device of any of 68-75 wherein the first material comprisesmultiple strands surrounded by the second material

77. The device of any of 68-75 wherein the multiple strands surroundedby the second material have a range coefficients of elongation such thatcomplex shape changes upon exposure to physiological fluid can beengineered.

78. The device of any of 68-75 wherein the multiple strands surroundedby the second material have a range of hydrolytic or enzymaticdegradation times to control shape changes during the degradationprocess.

79. The device of any of 50-75 wherein the therapeutic agent has asolubility in aqueous solution of no more than 10 micrograms permilliliter.

80. The method of any of 50-79 wherein the therapeutic agent is aprotein with MW greater than 1000 Da

81. The method of any of 50-80 wherein the therapeutic agent isencapsulated in a microparticle.

82. The device of any of 50-79 wherein the therapeutic agent comprisesan anti-angiogenic agent or other agent set forth herein.

83. The device of any of 50-82 wherein the therapeutic agent comprises atyrosine kinase inhibitor.

84. The device of any of 50-53 wherein the therapeutic agent comprises aanti-VEGF protein or antibody or aptamer.

85. The device of any of 50-53 wherein the therapeutic agent comprises aanti-PDGF protein or antibody or aptamer.

86. The device of any of 50-53 wherein the therapeutic agent comprises aanti-Ang2 protein or antibody or aptamer.

87. A device or a use of a device of any of 50-86 wherein the vehicle isintroduced at, in, or near an eye, into the conjunctiva, on the cornea,on a sclera, inside a sclera, on an interior wall of the eye,intraocular, intravitreal, on a retina, near a retina but not touching aretina, a distance of 1 to 2000 microns from a retina, suprachoroidal,in the choroidal, in a potential space, in a lumen artificially (by auser, with a tool) created to receive the vehicle, in a chamber of aneye, in the posterior chamber, in contact with vitreous humor, in thehyaline canal, or a combination thereof.

88. The device of any of 50-86 wherein the vehicle is introduced at, in,or near a vitreous humor or aqueous humor, Canaliculus, ampulla,Paranasal sinus, Joint capsules (e.g. knee, hip, etc.), Lumpectomy site,Biopsy site, Tumor core, Ear canal, Vaginal, Bladder, Esophageal,Bronchial, Abscesses, e.g. Dental, AV malformation sites, Vascularaneurysms or dissections, potential spaces, artificially created spacesor potential spaces, pessary, buccal, anal, uretheral, nasal, breast,iatrogenic, cancer, organs, luminal spaces, natural lumen, vascular,aneurysm.

89. A process of making a medical vehicle that changes shape uponexposure to aqueous solution comprising

-   -   stretching a polymeric material and drying it in the stretched        configuration,    -   joining two materials together that have different coefficients        of elongation, or    -   joining two materials together that have different coefficients        of coefficients of swelling.

90. The process of 89 comprising preparing the vehicle by stretching amaterial while wet and allowing the material to dry in the stretchedposition.

91. A process of making a solid medical vehicle that changes shape uponexposure to aqueous solution comprising

-   -   crosslinking a first polymeric material    -   stretching the first polymeric material to a stretched        configuration and, while the material is maintained under        tension or otherwise in the stretched configuration, making a        layer of a second crosslinked material that contacts the        stretched material,    -   herein the first material is chosen to decrease in length after        exposure to aqueous solution while it is in the stretched        configuration.

92. The process of 91 further comprising forming the first polymericmaterial and drying the material before and/or during and/or afterstretching the material.

93. The process of 91 or 92 further comprising, after forming the layer,drying the combined materials.

94. The process of any of 91-93 wherein the first material and thesecond material are independently chosen to be a hydrogel or anorganogel. 95. The process of any of 91-94 wherein the material isstretched by a factor between 2 and 10.

96. The process of any of 91-95 wherein the stretching of the materialcomprises forming zones of weakness in the material that result in acoiling of the vehicle upon exposure to physiological solution.

97. A process of making a solid medical vehicle that changes shape uponexposure to aqueous solution comprising

-   -   crosslinking a first polymeric material with a first swelling        coefficient.    -   crosslinking a layer of a second polymeric material that        contacts the first material with the second polymeric material        having a second swelling coefficient that is lower than the        first swelling coefficient,    -   wherein the first material changes in length to a lesser extent        than the second material after exposure to aqueous solution.

98. The process of 97 wherein the first material increases in lengthafter exposure to aqueous solution.

99. The process of 97 wherein the first material decreases in lengthafter exposure to aqueous solution.

100. The process of any of 97-99 wherein the second material increasesin length; alternatively, wherein the second material decreases inlength.

101. The process of any of 97-100 wherein the layers are formed within amold, e.g., a tubular mold, and the first polymeric material and thesecond polymeric material are introduced into the mold separately.

102. The process of any of 97-101 wherein the layers are formed within amold, e.g. a tubular mold, and the first polymeric material and thesecond polymeric material are introduced into the mold simultaneously.

103. The process of 102, wherein the introduction is performed utilizinglaminar flow to minimize mixing of the first polymeric material with thesecond polymeric material.

104. The process of any of 101-103 wherein the mold has a complex shape.

105. The process of any of 101-104 wherein, after at least partialcrosslinking in the mold, or after crosslinking, the crosslinked vehicleis further shaped by stretching.

106. The process of 105 wherein the shaping is performed while thematerials are a melt or while the materials are swollen in a solvent.

107. The process of 106 wherein the materials are cooled or dried toachieve a final shape, e.g., a fiber.

1. A process of making a solid shape-changing vehicle for delivery of atherapeutic agent to a tissue, comprising joining a first polymericmaterial having a first coefficient of swelling and/or a firstcoefficient of elongation to a second polymeric material having a secondcoefficient of swelling and/or a second coefficient of elongation, withthe therapeutic agent being disposed in the first material and/or thesecond material, wherein the solid vehicle changes shape after exposureto an aqueous solution, with the first material and the second materialdifferentially swelling and/or elongating in aqueous solution.
 2. Theprocess of claim 1 further comprising preparing the first polymericmaterial by crosslinking a precursor to form the first polymericmaterial and exposing the first polymeric material to a second precursorthat is crosslinked to form the second polymeric material, with thefirst polymeric material having the first coefficient of swelling andthe second polymeric material having the second coefficient of swelling,wherein the second coefficient of swelling is lower than the firstswelling coefficient and the second polymeric material changing inlength to a lesser extent than the second polymeric material afterexposure to aqueous solution.
 3. The process of claim 1 wherein thefirst material decreases in length after exposure to aqueous solution.4. The process of claim 3 wherein, after exposure to aqueous solution,the second material increases in length.
 5. The process of claim 1wherein the first polymeric material and the second polymeric materialare formed within a mold, and the first polymeric material and thesecond polymeric material are introduced into the mold separately orsimultaneously.
 6. The process of claim 5 further comprising stretchingthe joined materials after at least partially crosslinking the firstpolymeric material and the second polymeric material.
 7. The process of6 wherein the stretching is performed while the materials are heatedabove the melting points or while the materials are swollen in asolvent.
 8. The process of 7 further comprising cooling or drying of thejoined materials.
 9. The process of claim 1 wherein the first materialis formed by crosslinking a first precursor and at least one furtherprecursor and/or wherein the second material is formed by crosslinking asecond precursor and at least one further precursor.
 10. The process ofclaim 1 wherein the first material is formed by crosslinking a firstprecursor and further comprising stretching the first material, with thefirst material being semicrystalline and the stretching orientingcrystallites within the first material and/or with the stretchingcausing the first material to form a neck.
 11. The process of claim 1wherein the first material is formed by crosslinking a first precursorand further comprising (i) stretching the first material to form a notchin the first material or (ii) mechanically creating a notch in the firstmaterial.
 12. The process of claim 1 wherein the vehicle is a rod thathas an end that is cut at an angle of 30-60 degrees relative to aperpendicular cross-section.
 13. The process of claim 1 wherein thefirst material is provided as at least one rod and the second materialis a layer on the first material.
 14. The process of claim 1 with thevehicle forming a coil upon exposure to aqueous solution.
 15. Theprocess of claim 1 the vehicle is a xerogel that forms a hydrogel uponexposure to aqueous solution.
 16. A device for drug delivery comprisinga therapeutic agent disposed in a solid vehicle that changes shape inresponse to a physiological fluid and provides a controlled release ofthe therapeutic agent.
 17. The device of claim 16 wherein the vehicle isa rod with an aspect ratio of at least 1:10, before placement in aphysiological solution, wherein the device curls into a curved shape inresponse to a physiological solution.
 18. The device of claim 16 whereinthe vehicle is a xerogel that forms a hydrogel when exposed to aqueoussolution.
 19. The device of claim 16 wherein the vehicle comprises afirst and a second material that are joined together, wherein the firstmaterial has a first coefficient of elongation and/or a firstcoefficient of swelling in aqueous solution and the second material hasa second coefficient of elongation and/or a second coefficient ofswelling in aqueous solution, with first and second coefficients beingdifferent.
 20. The device of claim 19 forming a coil in aqueoussolution.
 21. The device of claim 20 with the vehicle forming a coilwithin 30 seconds of introduction to the aqueous solution.
 22. A methodof delivering a therapeutic agent to a patient comprising introducingthe device of claim 16 to an eye, into a conjunctiva, on a cornea, on asclera, inside a sclera, on an interior wall of an eye, intraocular,intravitreal, on a retina, near a retina but not touching a retina,suprachoroidal, in the choroid, in a potential space, in a lumen createdto receive the vehicle, in a chamber of an eye, in the posteriorchamber, in contact with vitreous humor, in the hyaline canal, in avitreous humor, in an aqueous humor, or at a tissue.